1
00:00:05,214 --> 00:00:08,384
SO GOOD AFTERNOON MY NAME IS KEN

2
00:00:08,384 --> 00:00:12,021
JACOBSEN IT IS MY GREAT PLEASURE

3
00:00:12,021 --> 00:00:20,496
TO INTRODUCE TODAY'S WALS

4
00:00:20,496 --> 00:00:21,664
SPEAKER, DANIELA SALVEMINI, I

5
00:00:21,664 --> 00:00:25,168
WAS ASKED TO GIVE THE LECTURE

6
00:00:25,168 --> 00:00:26,869
CODE 57679 AND ALSO THE END OF

7
00:00:26,869 --> 00:00:29,539
THE LECT YOU YOU CAN ASK A

8
00:00:29,539 --> 00:00:32,475
QUESTION IN PERSON OR SUBMIT A

9
00:00:32,475 --> 00:00:35,745
QUESTION ONLINE USING THE "SEND

10
00:00:35,745 --> 00:00:37,246
LIVE FEEDBACK BUTTON" ON THE

11
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VIDEO PAGE.

12
00:00:39,082 --> 00:00:41,250
FOLLOWING THE PRESENTATION THERE

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WILL BE A RECEPTION OUTSIDE THE

14
00:00:45,788 --> 00:00:47,490
OWDITORIUM.

15
00:00:47,490 --> 00:00:49,625
SO DR. SALVEMINI IS A LONG-TERM

16
00:00:49,625 --> 00:00:52,728
COLLABORATOR OF OURS AND I KNOW

17
00:00:52,728 --> 00:00:55,297
HER EXCITEMENT RELATED TO

18
00:00:55,297 --> 00:00:55,531
GCPRs.

19
00:00:55,531 --> 00:00:59,802
SHE'S CURRENTLY THE WIMIAM

20
00:00:59,802 --> 00:01:01,737
BEAUMONT CHAIR OF PHARMACOLOGY

21
00:01:01,737 --> 00:01:02,438
AND PHYSIOLOGY.

22
00:01:02,438 --> 00:01:03,739
FOUNDING DIRECTOR FOR

23
00:01:03,739 --> 00:01:04,406
INSTITUTIONAL TRANSLATIONAL

24
00:01:04,406 --> 00:01:09,078
SCIENCE AT ST. LOUIS UNIVERSITY,

25
00:01:09,078 --> 00:01:13,349
DR. SALVEMINI RECEIVED HER BSC

26
00:01:13,349 --> 00:01:15,017
IN PHARMACOLOGY AND Ph.D. FROM

27
00:01:15,017 --> 00:01:16,252
UNIVERSITY THE LONDON.

28
00:01:16,252 --> 00:01:18,220
SHE EARNED IT UNDER THE

29
00:01:18,220 --> 00:01:19,688
MENTORSHIP OF PROFESSOR SHIRR

30
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JOHN VAIN WHO WON THE NOBEL

31
00:01:24,193 --> 00:01:26,195
PRIZE FOR ELUCIDATING EFFECTS OF

32
00:01:26,195 --> 00:01:26,862
PROOF THE GLANDINS.

33
00:01:26,862 --> 00:01:28,297
A LOST THINGS WE TAKE FOR

34
00:01:28,297 --> 00:01:33,102
GRANTED NOW, WE HAVE TO STUDY

35
00:01:33,102 --> 00:01:34,370
THE HISTORY.

36
00:01:34,370 --> 00:01:37,406
SHE PURSUED POST DOCTORAL AT

37
00:01:37,406 --> 00:01:41,076
LOPPED AN RESEARCH INSTITUTE AND

38
00:01:41,076 --> 00:01:43,946
AT MONSANTO IN THE STOEVERY OF

39
00:01:43,946 --> 00:01:46,182
PHARMACOLOGY BEFORE JOINING

40
00:01:46,182 --> 00:01:47,449
ST. LOUIS UNIVERSITY HER

41
00:01:47,449 --> 00:01:48,951
RESEARCH INTERESTS NEAR

42
00:01:48,951 --> 00:01:50,819
UNDERSTANDING THE MOLECULAR

43
00:01:50,819 --> 00:01:51,854
MECHANISMS INVOLVED IN

44
00:01:51,854 --> 00:01:53,589
NEUROPATHIC PAIN STATES AND

45
00:01:53,589 --> 00:01:55,224
DISCOVERY OF NONOPIOID

46
00:01:55,224 --> 00:01:58,160
THERAPEUTICS, TO ADDRESS A MAJOR

47
00:01:58,160 --> 00:02:01,463
UNMET MEDICAL NEED, AND HELP AND

48
00:02:01,463 --> 00:02:03,299
HUMAN SUFFERING.

49
00:02:03,299 --> 00:02:04,700
SHE SERVES UNDER NUMEROUS

50
00:02:04,700 --> 00:02:06,135
COMMITTEES AND BOARDS INCLUDING

51
00:02:06,135 --> 00:02:09,738
THE NIH STUDY SECTIONS AT NIDA,

52
00:02:09,738 --> 00:02:11,173
NCI AND NINDS, SHE'S THE FOUNDER

53
00:02:11,173 --> 00:02:16,845
OF 2 START UP COMPANIES:  BY O

54
00:02:16,845 --> 00:02:18,280
INTERVENE IS IDENTIFYING

55
00:02:18,280 --> 00:02:20,149
RECEPTOR AGONISTS FOR

56
00:02:20,149 --> 00:02:23,385
NEUROPATHIC PAIN AND

57
00:02:23,385 --> 00:02:24,453
NEUROINFLAMMATORY DECS INVINCION

58
00:02:24,453 --> 00:02:26,155
INCORPORATED THAT IS DEVELOPING

59
00:02:26,155 --> 00:02:27,690
NOVEL THERAPIES FOR PAIN AND

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00:02:27,690 --> 00:02:27,923
CANCER.

61
00:02:27,923 --> 00:02:31,527
SHE'S ALSO THE FOUNDER OF THE

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00:02:31,527 --> 00:02:32,261
ST. LOUIS TRANSLATIONAL PAIN

63
00:02:32,261 --> 00:02:33,963
RESEARCH FORUM.

64
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SHE'S HAD MANY AWARDS INCLUDING

65
00:02:37,032 --> 00:02:39,468
THE NOVARTIS AWARD IN

66
00:02:39,468 --> 00:02:40,002
PHARMACOLOGY, OUTSTANDING

67
00:02:40,002 --> 00:02:41,604
SCIENTIST AWARD FROM THE

68
00:02:41,604 --> 00:02:44,807
ST. LOUIS ACADEMY OF SCIENCE,

69
00:02:44,807 --> 00:02:46,742
PHARMACY AWARD IN EXPERIMENTAL

70
00:02:46,742 --> 00:02:48,644
THERAPEUTICS AND THE MITCHELL B

71
00:02:48,644 --> 00:02:50,412
MAX AWARD FOR PAIN FROM THE

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00:02:50,412 --> 00:02:52,581
AMERICAN ACADEMY OF NEUROLOGY,

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SHE'S A FELLOW OF THE ST. LOUIS

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00:02:55,718 --> 00:02:56,885
ACADEMY OF SCIENCE AND ALSO

75
00:02:56,885 --> 00:02:59,154
FELLOW OF THE NATIONAL ACADEMY

76
00:02:59,154 --> 00:03:01,590
OF INVENTORS AND ALSO THE FELLOW

77
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RESEARCH INSTITUTE, FINALLY,

78
00:03:02,891 --> 00:03:04,393
RECENTLY SHE WAS MADE A FELLOW

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00:03:04,393 --> 00:03:06,629
OF THE AMERICAN SOCIETY OF

80
00:03:06,629 --> 00:03:11,100
FORMICOLOGY AND EXPERIMENTAL

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00:03:11,100 --> 00:03:19,775
THERAPEUTICS ASSPEC.

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00:03:19,775 --> 00:03:28,384
DR. SALVEMINI, HAS STUDY THE

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00:03:28,384 --> 00:03:29,652
SPHINGOPATHY AND I NOW INVITE

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00:03:29,652 --> 00:03:33,522
HER TO DELIVER THE LECTURE.

85
00:03:33,522 --> 00:03:34,356
[ APPLAUSE ]

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00:03:34,356 --> 00:03:42,097
>> THAIRNG YOU  -- THANK
YOU VEY

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00:03:42,097 --> 00:03:43,766
MUCH DR. JACOBSEN AND ALL THE

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00:03:43,766 --> 00:03:44,600
ORGANIZERS AND IT'S A PLEASURE

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00:03:44,600 --> 00:03:46,201
TO BE HERE AND DELIVER THIS

90
00:03:46,201 --> 00:03:47,569
LECTURE, SO FAR I HAD A

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00:03:47,569 --> 00:03:49,438
BEAUTIFUL DAY.

92
00:03:49,438 --> 00:03:51,974
MET WITH WONDERFUL STUDENTS AND

93
00:03:51,974 --> 00:03:53,409
PIs AND I'M LOOKING FORWARD TO

94
00:03:53,409 --> 00:03:58,013
THE REST OF THE DAY SO AS

95
00:03:58,013 --> 00:03:59,148
DR. JAIB OBSESSIVESSEN MENTIONED

96
00:03:59,148 --> 00:04:01,150
WE ARE VERY MUCH INTERESTED IN

97
00:04:01,150 --> 00:04:02,885
GPC Rs AND TODAY I WILL GIVE

98
00:04:02,885 --> 00:04:04,953
YOU AN OVERVIEW OF 1 OF MY

99
00:04:04,953 --> 00:04:06,255
FAVORITE PROJECTS THAT I STARTED

100
00:04:06,255 --> 00:04:08,324
15 YEARS AGO IN ABOUT 45 MINUTES

101
00:04:08,324 --> 00:04:09,958
SO I HAD TO KIND OF PICK AND

102
00:04:09,958 --> 00:04:10,959
CHOOSE THE SLIDES THAT I WANTED

103
00:04:10,959 --> 00:04:13,128
TO SHOW YOU TO CONVEY OUR

104
00:04:13,128 --> 00:04:15,197
MESSAGE BUT REALLY THE TAKE HOME

105
00:04:15,197 --> 00:04:16,899
MESSAGE HERE IS THAT I WOULD

106
00:04:16,899 --> 00:04:19,968
LIKE TO PROPOSE THAT WE SHOULD

107
00:04:19,968 --> 00:04:22,838
CONSIDER SOME TYPES OF

108
00:04:22,838 --> 00:04:23,906
NEUROPATHIC PAIN CONDITIONS AS

109
00:04:23,906 --> 00:04:27,009
SPHING OPEN MEETINGATHYS THAT

110
00:04:27,009 --> 00:04:28,344
ARE THAT ARE TO THE THERAPIES

111
00:04:28,344 --> 00:04:33,215
AND THIS IS REALLY MY STORY.

112
00:04:33,215 --> 00:04:34,750
SO MOST OF YOU KNOW THAT CHRONIC

113
00:04:34,750 --> 00:04:36,685
PAIN IS A DISEASE, CAN YOU SEE

114
00:04:36,685 --> 00:04:37,086
MY POINTER?

115
00:04:37,086 --> 00:04:38,787
IT IS 1 OF THE MOST SIGNIFICANT

116
00:04:38,787 --> 00:04:40,356
HEALTH ISSUES IN THE GLOBE,

117
00:04:40,356 --> 00:04:42,691
AFFECTS MILLIONS OF INDIVIDUALS

118
00:04:42,691 --> 00:04:45,394
AROUND THE UNITED STATES

119
00:04:45,394 --> 00:04:46,895
AFFECTING BILLIONS OF DOLLARS

120
00:04:46,895 --> 00:04:48,864
EACH YEAR IN MEDICAL TREATMENTS,

121
00:04:48,864 --> 00:04:51,767
CHRONIC PAIN IS ALSO LINKED TO

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00:04:51,767 --> 00:04:53,736
ANXIETY, DEPRESSION, OBESITY,

123
00:04:53,736 --> 00:04:57,639
STRESS, SLEEP DISPUSHANCES AND

124
00:04:57,639 --> 00:04:58,841
MECHANISMS REMAIN OBSCURE.

125
00:04:58,841 --> 00:05:00,876
SO THE RESEARCH INTEREST IN MY

126
00:05:00,876 --> 00:05:02,544
LABS ARE REALLY KIND OF STRAIGHT

127
00:05:02,544 --> 00:05:05,514
FORWARD, WE WANT TO TARGET

128
00:05:05,514 --> 00:05:06,348
CHRONIC NEUROPATHIC PAIN STATES

129
00:05:06,348 --> 00:05:08,650
TO ADDRESS A BIG MEDICAL NEED.

130
00:05:08,650 --> 00:05:11,286
WE WANT TO UNDERSTAND AND

131
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DECIPHER MOST THE MOLECULAR AND

132
00:05:14,189 --> 00:05:15,557
SINGLE MECHANISMS UNDERPINNING

133
00:05:15,557 --> 00:05:17,393
YOUR PATH STATES AND WE WANT TO

134
00:05:17,393 --> 00:05:20,996
DISCOVER SAFE AND EFFICACIOUS

135
00:05:20,996 --> 00:05:22,398
NONOPIOID BASED THERAPY.

136
00:05:22,398 --> 00:05:23,532
EVERY DISCOVERED BIOMARKERS THAT

137
00:05:23,532 --> 00:05:25,501
WOULD ALLOW US TO CATEGORIZE THE

138
00:05:25,501 --> 00:05:27,569
PATIENTS SO AS TO PROVIDE

139
00:05:27,569 --> 00:05:28,404
PERSONALIZE TREATMENT AND THEN

140
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WE WANT TO TRANSLATE DORPHY FROM

141
00:05:30,939 --> 00:05:34,209
BENCH TO CLINICAL TRIALS.

142
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SO AS DR. JACOBSEN SAID, WE

143
00:05:44,219 --> 00:05:45,587
STARTED STUDYING THIS AND WE ARE

144
00:05:45,587 --> 00:05:47,990
INTERESTED IN THE OXIDATIVE

145
00:05:47,990 --> 00:05:49,625
STRESS, SO PURPOSE FOR TODAY I

146
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WILL FOCUS ON 1 OF THE GPC Rs,

147
00:05:52,528 --> 00:05:54,062
BEFORE I DO THAT, LET ME TALK

148
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ABOUT PAIN.

149
00:05:57,433 --> 00:05:59,067
THIS AFFECTS 700 MILLION PEOPLE

150
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WORLD WIDE, I'M ATTACHED TO

151
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NEUROPATHIC PAIN BECAUSE IT'S 1

152
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OF THE MOST DIFFICULT PAIN

153
00:06:03,439 --> 00:06:04,640
STATES TO ACTUALLY ADDRESS.

154
00:06:04,640 --> 00:06:07,509
MORE OVER, AS YOU PROBABLY KNOW,

155
00:06:07,509 --> 00:06:11,914
THE CURRENT MEDICATIONS DO NOT

156
00:06:11,914 --> 00:06:13,348
PROVIDE ADEQUATE PAIN RELIEF AND

157
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HAVE A VARIETY OF SIDE EFFECTS,

158
00:06:14,950 --> 00:06:19,087
SO THIS IS A SLIDE THAT WAS

159
00:06:19,087 --> 00:06:20,689
PUBLISHED BY BANNISTER IN 2020,

160
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IT WAS NOT MUCH TO UPDATE IN THE

161
00:06:22,458 --> 00:06:24,259
LAST 5 YEARS AND AS CAN YOU

162
00:06:24,259 --> 00:06:26,728
PROBABLY SEE IT IS A VERY SLAD

163
00:06:26,728 --> 00:06:36,371
SLIDE BECAUSE IT SHOWS YOU AND

164
00:06:36,371 --> 00:06:37,206
YOUR YOUR ANTIDEPRESSANTS.

165
00:06:37,206 --> 00:06:40,876
WE KNOW THE PROBLEM THAT OPIOIDS

166
00:06:40,876 --> 00:06:43,412
HAVE DONE IN PAIN IN GENERAL BAH

167
00:06:43,412 --> 00:06:44,279
ALSO IN NEUROPATHIC PAIN BECAUSE

168
00:06:44,279 --> 00:06:46,615
WHEN YOU LOOK AT THE USE OF

169
00:06:46,615 --> 00:06:48,484
OPIOIDS IN 92URE O PATHIC PAIN,

170
00:06:48,484 --> 00:06:50,886
YOU WILL SEE THAT A GREAT

171
00:06:50,886 --> 00:06:52,488
PROPORTION OF PATIENTS THAT EVEN

172
00:06:52,488 --> 00:06:54,890
THOUGH MILD TO MODERATE PAIN

173
00:06:54,890 --> 00:06:56,658
SETTINGS, THEY ARE PRESCRIBED A

174
00:06:56,658 --> 00:07:01,230
LOT OF OPIOID, SO IT'S BEEN A

175
00:07:01,230 --> 00:07:02,097
BIG PROBLEM.

176
00:07:02,097 --> 00:07:04,933
WHAT WE DO KNOW THOUGH IS THAT

177
00:07:04,933 --> 00:07:06,869
FOR THE MOST PART THESE CURRENT

178
00:07:06,869 --> 00:07:10,239
DRUGS THAT WE USE AFFECTS MAINLY

179
00:07:10,239 --> 00:07:11,106
NEURONS, OKAY?

180
00:07:11,106 --> 00:07:13,408
HOWEVER, WE KNOW FROM THE LAST

181
00:07:13,408 --> 00:07:17,012
10 YEARS OR SO THAT NONNEURONAL

182
00:07:17,012 --> 00:07:19,848
CELLS CONTRIBUTE TO CENTRAL

183
00:07:19,848 --> 00:07:20,716
DESENSITIZATION BY ENGAGING

184
00:07:20,716 --> 00:07:22,217
NEURAL INFLAMMATION IN THE

185
00:07:22,217 --> 00:07:22,885
CENTRAL NERVOUS SYSTEM.

186
00:07:22,885 --> 00:07:24,052
SO WE KNOW FOR EXAMPLE, CELLS

187
00:07:24,052 --> 00:07:26,588
THAT ARE IN THE CENTRAL NERVOUS

188
00:07:26,588 --> 00:07:29,892
SYSTEM, FOR EXAMPLE IN THE

189
00:07:29,892 --> 00:07:32,861
SPINAL CORD AND MICROGLIAL CELLS

190
00:07:32,861 --> 00:07:33,996
REGULATE NEURONAL EXCITABILITY

191
00:07:33,996 --> 00:07:35,330
BY THE RELEASE OF SEVERAL

192
00:07:35,330 --> 00:07:37,165
SUBSTANCES, SOME OF THEM CAN BE

193
00:07:37,165 --> 00:07:39,301
CYTOKINES SUCH AS FOR EXAMPLE,

194
00:07:39,301 --> 00:07:41,737
IL1 BETA XI WILL TALK TO YOU

195
00:07:41,737 --> 00:07:44,873
MORE ABOUT IL1 BETA BUT IT CAN

196
00:07:44,873 --> 00:07:45,707
INCREASE NEURONAL EXCITABILITY

197
00:07:45,707 --> 00:07:47,676
BI FOR EXAMPLE, ACTIVATING ERK,

198
00:07:47,676 --> 00:07:50,312
WHICH INTURN CAN AFFECT THE

199
00:07:50,312 --> 00:07:51,880
ACTIVITY OF THE NMDA RECEPTORS

200
00:07:51,880 --> 00:07:53,949
AND SO THIS WILL THEN RESPOND

201
00:07:53,949 --> 00:07:56,652
MORE AGGRESSIVELY FOR EXAMPLE,

202
00:07:56,652 --> 00:07:57,452
SYNAPTIC NEURAL TRANSMISSION.

203
00:07:57,452 --> 00:07:59,154
AT THE SAME TIME THIS KIND OF

204
00:07:59,154 --> 00:08:01,790
CELLS CAN ALSO RELEASE E ACTIVE

205
00:08:01,790 --> 00:08:08,263
OXYGEN SPECIES WHICH CAN NITRATE

206
00:08:08,263 --> 00:08:11,066
AND DEACTIVATE ASTRO CITE

207
00:08:11,066 --> 00:08:12,000
TRANSPORTERS TO HAVE SYNAPSE

208
00:08:12,000 --> 00:08:13,735
WITH THE MORE GLUTAMATE PRESENT

209
00:08:13,735 --> 00:08:17,406
IN THE SYNAPSE AND INCREASED

210
00:08:17,406 --> 00:08:18,473
NEURONAL EXCITABILITY.

211
00:08:18,473 --> 00:08:20,576
AT THE SAME TIME THESE CELLS ARE

212
00:08:20,576 --> 00:08:22,010
ACTIVATED, AS A PROTECTIVE

213
00:08:22,010 --> 00:08:23,545
MECHANISM THEY WILL RELEASE

214
00:08:23,545 --> 00:08:24,379
NEUROPROTECTIVE MOLECULES AND I

215
00:08:24,379 --> 00:08:25,948
AM SHOWING YOU HERE WOON THAT WE

216
00:08:25,948 --> 00:08:27,115
ARE REALLY EXCITED AND REALLY

217
00:08:27,115 --> 00:08:30,218
LIKE IS IRPT LUKEIN 10, SO

218
00:08:30,218 --> 00:08:32,554
INTERLEUKIN 10 IS FIEWR O

219
00:08:32,554 --> 00:08:34,256
PROTECTIVE AND INHIBITS

220
00:08:34,256 --> 00:08:34,856
NEURONONAL EXCITABILITY.

221
00:08:34,856 --> 00:08:36,625
SO THE CELLS ARE EXCITED, THEY

222
00:08:36,625 --> 00:08:39,127
RELEASE A LOT OF PROINFLAMMATORY

223
00:08:39,127 --> 00:08:42,898
CYTOKINES BUT THEY ALSO RELEASE

224
00:08:42,898 --> 00:08:43,799
ANTIBIN FLAMMATORY CYTOKINES TO

225
00:08:43,799 --> 00:08:45,467
TRY TO DAMPEN THE EXTENT OF THE

226
00:08:45,467 --> 00:08:46,868
PROCESS EMPLOY WE ALSO KNOW IN

227
00:08:46,868 --> 00:08:48,537
PRESPONSE TO NERVE YOUR OR CHEMO

228
00:08:48,537 --> 00:08:50,505
THERAPY FOR EXAMPLE, YOU HAVE

229
00:08:50,505 --> 00:08:52,174
INFILTRATING, IT CELLS IN THE

230
00:08:52,174 --> 00:08:56,011
CENTRAL NERVOUS SYSTEM THAT CAN

231
00:08:56,011 --> 00:08:57,646
ALSO INCREASE AND NEURONAL

232
00:08:57,646 --> 00:08:58,981
EXCITABILITY, SO TO MAKE A LONG

233
00:08:58,981 --> 00:09:00,916
STORY SHORT, WHAT WE KNOW NOW IS

234
00:09:00,916 --> 00:09:02,718
THAT NO NEURONAL CELLS HAVE MANY

235
00:09:02,718 --> 00:09:04,720
RECEPTORS THAT RESPONDS TO

236
00:09:04,720 --> 00:09:07,189
MEDIATORS, RELEASED IN RESPONSE

237
00:09:07,189 --> 00:09:09,324
TO NOXIOUS STIMULI BY LOCALLY

238
00:09:09,324 --> 00:09:10,926
ACTIVATED NEURONS ARE ALSO FOUND

239
00:09:10,926 --> 00:09:11,593
WITHIN THE CIRCULATION, TAKE

240
00:09:11,593 --> 00:09:13,629
EXAMPLE OF THE USE OF CHEMO

241
00:09:13,629 --> 00:09:15,964
THERAPY FOR EXAMPLE, CHEEM OR

242
00:09:15,964 --> 00:09:18,166
THERAPY RELEASES CYTOKINES IN

243
00:09:18,166 --> 00:09:19,468
THE CIRCULATION, THESE CYTOKINES

244
00:09:19,468 --> 00:09:20,636
ACCESS THE CENTRAL NERVOUS

245
00:09:20,636 --> 00:09:23,171
SYSTEM WHERE THEY CAN THEN

246
00:09:23,171 --> 00:09:24,806
ACTIVATE DIRECT NEURONS OR TURN

247
00:09:24,806 --> 00:09:27,576
ON THESE NONIMMUNE CELLS, SO IN

248
00:09:27,576 --> 00:09:29,111
ESSENCE THESE NONNEURONAL CELLS

249
00:09:29,111 --> 00:09:31,546
ACCELERATE THE PAIN SYSTEM TO AN

250
00:09:31,546 --> 00:09:34,249
ENDLESS INFLMA ARE TOY LOOP THAT

251
00:09:34,249 --> 00:09:36,551
PROVOKES NERVES INTO GENERATING

252
00:09:36,551 --> 00:09:37,819
A   PERPETUAL PAIN ALARM.

253
00:09:37,819 --> 00:09:39,354
SO SOMETHING THAT WE'VE BEEN

254
00:09:39,354 --> 00:09:41,289
ASKING OURSELVES IS, CAN WE

255
00:09:41,289 --> 00:09:43,859
TREAT THE NEUROPATHIC PAIN BY

256
00:09:43,859 --> 00:09:45,794
COUNTER BALANCING NEURAL

257
00:09:45,794 --> 00:09:47,095
INFLAMMATION THROUGH CELL

258
00:09:47,095 --> 00:09:48,597
SPECIFIC GPC Rs ACTIVATION OR

259
00:09:48,597 --> 00:09:51,767
INHIBITION AND AS I SAID WE HAVE

260
00:09:51,767 --> 00:09:52,401
SEVERAL PROGRAMS HERE.

261
00:09:52,401 --> 00:09:54,936
AND I THINK THAT THAT WE CAN AND

262
00:09:54,936 --> 00:09:56,905
THATORY THAT I WILL PROVIDE

263
00:09:56,905 --> 00:09:58,640
TODAY, IS THAT WE THINK THAT WE

264
00:09:58,640 --> 00:10:01,643
CAN DO THAT BY TARGETING THIS

265
00:10:01,643 --> 00:10:05,247
RECEPTOR CALLED S1 PR1 ON ASTRO

266
00:10:05,247 --> 00:10:05,647
SIGHTS.

267
00:10:05,647 --> 00:10:05,881
OKAY?

268
00:10:05,881 --> 00:10:08,417
SO FOR THOSE OF YOU THAT ARE

269
00:10:08,417 --> 00:10:10,585
FAMILIAR WITH SINGLE LIPID

270
00:10:10,585 --> 00:10:12,154
METABOLISM, THEY'RE VERY, VERY

271
00:10:12,154 --> 00:10:13,188
COMPLICATED SPECIES TO STUDY.

272
00:10:13,188 --> 00:10:15,724
SOME OF THE MOST WELL STUDIED OF

273
00:10:15,724 --> 00:10:17,325
THE SINGLE LIPIDS ARE SERIES

274
00:10:17,325 --> 00:10:18,493
POINTS MID AND S1 P.

275
00:10:18,493 --> 00:10:22,230
SO THIS IS A SIMPLISTIC OVERVIEW

276
00:10:22,230 --> 00:10:23,331
OF THE PATHWAY, SO BASICALLY

277
00:10:23,331 --> 00:10:25,400
WHAT HAPPENS IS WHEN YOU HAVE A

278
00:10:25,400 --> 00:10:26,935
STIMULI, YOU MAKE SERIES POINTS

279
00:10:26,935 --> 00:10:30,338
MID, BY ACTIVATING THE SINGLE

280
00:10:30,338 --> 00:10:32,974
MILEN PATHWAY, BY THESE OR BY

281
00:10:32,974 --> 00:10:35,043
ACTIVATING THE DE NOVO PATHWAY

282
00:10:35,043 --> 00:10:36,878
BY TURNING ON TRANSFER ACE WHICH

283
00:10:36,878 --> 00:10:38,714
IS THE RATE LIMITING ENZYME IN

284
00:10:38,714 --> 00:10:39,781
THE PRODUCTION OF SERIES POINTS

285
00:10:39,781 --> 00:10:40,048
MID.

286
00:10:40,048 --> 00:10:47,155
NO SERIES POINTS MID IS

287
00:10:47,155 --> 00:10:49,357
CONVERTED BY SEVERAL SPHINGO

288
00:10:49,357 --> 00:10:53,061
THEN IS PHOSPHORYLATED IN

289
00:10:53,061 --> 00:10:55,163
KINASES, SPHINGO IN KINASE 1

290
00:10:55,163 --> 00:10:57,332
INVOLVED IN INFLAMMATION TO MAKE

291
00:10:57,332 --> 00:11:00,202
THE S1 P, S1 P THEN CAN ACTIVATE

292
00:11:00,202 --> 00:11:04,840
5 DIFFERENT TYPES OF GPC Rs,

293
00:11:04,840 --> 00:11:07,609
S1 PR1 THROUGH 5 AND THEN SIGNAL

294
00:11:07,609 --> 00:11:09,244
IS TERMINATED BY S1 P BEING

295
00:11:09,244 --> 00:11:10,512
DEGREATED BOO I A VARIETY OF

296
00:11:10,512 --> 00:11:14,816
FOSTER 

297
00:11:14,816 --> 00:11:15,383
PHOSPHATASES AND LIGASES.

298
00:11:15,383 --> 00:11:16,918
SO OVER THE LAST 14 YEARS AND I

299
00:11:16,918 --> 00:11:18,520
DON'T HAVE TIME TO TELL YOU HOW

300
00:11:18,520 --> 00:11:20,088
I ACTUALLY GOT MYSELF INTERESTED

301
00:11:20,088 --> 00:11:22,390
IN THIS PATHWAY BUT IT WAS

302
00:11:22,390 --> 00:11:24,993
ACTUALLY BY MISTAKE AND I'M GLAD

303
00:11:24,993 --> 00:11:26,728
THAT THIS MISTAKE SPANNED OUT

304
00:11:26,728 --> 00:11:28,463
BUT BASICALLY WHAT WE FOUND OVER

305
00:11:28,463 --> 00:11:30,198
THE LAST 14 YEARS IS SHOWN IN

306
00:11:30,198 --> 00:11:30,732
THIS SLIDE.

307
00:11:30,732 --> 00:11:34,002
WHAT WE FOUND WAS THAT TRAUMATIC

308
00:11:34,002 --> 00:11:35,704
NERVE INJURIES, CHEMO

309
00:11:35,704 --> 00:11:39,241
THERAPEUTICS AND EVEN OPIOIDS

310
00:11:39,241 --> 00:11:40,876
CAN TURN ON SINGLE METABOLISM IN

311
00:11:40,876 --> 00:11:44,880
THE SYSTEM AND GENERATE S1

312
00:11:44,880 --> 00:11:46,281
PWHICH CAN DRIVE NEUROPATHIN

313
00:11:46,281 --> 00:11:49,851
PAIN STATES BY ACTIVATING THE

314
00:11:49,851 --> 00:11:51,153
SPR1 RECEPTOR AND THIS THE IS

315
00:11:51,153 --> 00:11:53,455
STORY I WILL SHOW YOU TODAY.

316
00:11:53,455 --> 00:11:55,323
SO REMEMBER WHEN WE TARTED IN

317
00:11:55,323 --> 00:11:56,725
2008, THERE WAS ABSOLUTELY

318
00:11:56,725 --> 00:11:57,993
NOTHING KNOWN ABOUT THE ROLE OF

319
00:11:57,993 --> 00:12:01,396
THIS PATHWAY IN PAIN IN GENERAL

320
00:12:01,396 --> 00:12:02,864
AND SPECIFICALLY IN NEUROPATHIC

321
00:12:02,864 --> 00:12:06,601
PAIN STATES SO WE HAD TO TART

322
00:12:06,601 --> 00:12:07,035
FROM SCRATCH.

323
00:12:07,035 --> 00:12:08,403
SO 1 OF THE FIRST THINGS WE DID

324
00:12:08,403 --> 00:12:11,506
AT A TIME WAS TO SAY, OKAY, IS

325
00:12:11,506 --> 00:12:13,408
THIS S1 P EXPRESSED ALONG THE

326
00:12:13,408 --> 00:12:15,644
PAIN NEURAL ACCESS AND IS IT

327
00:12:15,644 --> 00:12:16,578
EXPRESSING RELEVANT CELLS CROSS

328
00:12:16,578 --> 00:12:17,846
LINKING THE ANSWER TO THAT

329
00:12:17,846 --> 00:12:20,248
QUESTION IS YES, IT IS PRESENT

330
00:12:20,248 --> 00:12:21,650
ABUNDANTLY IN THE SPINAL CORD

331
00:12:21,650 --> 00:12:23,518
WITH BOTH OF RODENTS AS WELL AS

332
00:12:23,518 --> 00:12:26,588
MICE, AS WELL AS IN SUPER SPINAL

333
00:12:26,588 --> 00:12:29,391
SITES SUCH AS IN THE RVM,

334
00:12:29,391 --> 00:12:30,659
IMPORTANTLY, THE RECEPTOR IS

335
00:12:30,659 --> 00:12:34,095
EXPRESSED IN GLIAL CELLS SO

336
00:12:34,095 --> 00:12:38,567
THESE NONMUTANT DISEASE CELLS,

337
00:12:38,567 --> 00:12:40,402
WHERE THEY FACILITATE AND WHERE

338
00:12:40,402 --> 00:12:43,305
THEY HAVE AN INFLAMMATORY

339
00:12:43,305 --> 00:12:44,206
PHENOTYPE.

340
00:12:44,206 --> 00:12:45,473
BUT WHAT'S REALLY, REALLY

341
00:12:45,473 --> 00:12:46,908
EXCITING WAS THIS WAS HIGHLY

342
00:12:46,908 --> 00:12:48,910
EXPRESSED IN THE ASTRO SIGHTS

343
00:12:48,910 --> 00:12:51,713
BOTH IN HUMANS AS WELL AS IN

344
00:12:51,713 --> 00:12:54,082
RODENTS, MINIMAL EXPRESSION, IN

345
00:12:54,082 --> 00:12:56,251
THE NEURON, SO KNOWING THAT THE

346
00:12:56,251 --> 00:12:58,453
RECEPTOR IS EXPRESSED BOTH IN

347
00:12:58,453 --> 00:13:00,889
HUMANS AND IN RODENTS AT

348
00:13:00,889 --> 00:13:03,325
IMPORTANT SITES, WE THEN STARTED

349
00:13:03,325 --> 00:13:04,459
EXPLORING THE POTENTIAL

350
00:13:04,459 --> 00:13:07,562
CONTRIBUTION OF THE SYSTEM IN

351
00:13:07,562 --> 00:13:08,396
NEUROPATHIC PAIN STATES, 1 OF

352
00:13:08,396 --> 00:13:09,698
THE MANY MODELS THAT WE HAVE IN

353
00:13:09,698 --> 00:13:12,234
THE LAB, IS THIS MODEL, SOME OF

354
00:13:12,234 --> 00:13:14,436
YOU ARE FAMILIAR, CALLED

355
00:13:14,436 --> 00:13:19,708
CONSTRICTION INJURY, WHERE WE

356
00:13:19,708 --> 00:13:23,645
BASICALLY LIGATE THE SCIATIC

357
00:13:23,645 --> 00:13:27,115
NERVE OF A MOUSE OR RAT, WE

358
00:13:27,115 --> 00:13:28,516
INFLATE THE NERVE, INFLATION

359
00:13:28,516 --> 00:13:32,020
AROUND THE NURVE, THEN THEY

360
00:13:32,020 --> 00:13:34,656
DEVELOP ALOE DEANIA, EXAGGERATED

361
00:13:34,656 --> 00:13:37,659
RESPONSE TO STIMULI THAT IS

362
00:13:37,659 --> 00:13:39,394
INNOCUOUS AND HYPER ALGEEZIA

363
00:13:39,394 --> 00:13:40,795
WHICH IS AN EXAGGERATED RESPONSE

364
00:13:40,795 --> 00:13:42,397
TO SOMETHING THAT IS ALREADY

365
00:13:42,397 --> 00:13:44,399
NOXIOUS AND THIS IS SOME OF THE

366
00:13:44,399 --> 00:13:46,034
BEHAVIORIAL PHENOTYPES THAT

367
00:13:46,034 --> 00:13:47,769
PATIENTS WITH NEUROPATHIC PAIN

368
00:13:47,769 --> 00:13:48,136
EXHIBIT.

369
00:13:48,136 --> 00:13:50,438
SO WHAT YOU SEE HERE, IF THE

370
00:13:50,438 --> 00:13:53,408
LINE GOES DOWN, THAT MEANS MORE

371
00:13:53,408 --> 00:13:53,875
PAIN, OKAY?

372
00:13:53,875 --> 00:13:57,913
SO WE DO THE INJURY TO -- THIS

373
00:13:57,913 --> 00:14:00,015
IS A RAT, AND YOU CAN THAT ABOUT

374
00:14:00,015 --> 00:14:01,983
7 DAYS AFTER THAT YOU HAVE THE

375
00:14:01,983 --> 00:14:03,385
DEVELOPMENT OF SEVERE PAIN, I

376
00:14:03,385 --> 00:14:07,055
JUST USE THE WORD PAIN JUST FOR

377
00:14:07,055 --> 00:14:07,422
SIMPLICITY.

378
00:14:07,422 --> 00:14:08,356
SO SIGNIFICANT DEVELOPMENT OF

379
00:14:08,356 --> 00:14:09,457
THE PAIN RESPONSE AND THEN WHAT

380
00:14:09,457 --> 00:14:12,227
WE DID WAS WE ISOLATED, WE

381
00:14:12,227 --> 00:14:13,862
HARVESTED, THE DORSAL HORN OF

382
00:14:13,862 --> 00:14:18,166
THE SPINAL CORD, AND ASKED WHEN

383
00:14:18,166 --> 00:14:20,001
THE ENZYMES THAT ARE INVOFFED IN

384
00:14:20,001 --> 00:14:22,304
THE PRODUCTION OF SERIES POINTS

385
00:14:22,304 --> 00:14:26,074
MID AND S1 P ARE TURNED ON AND

386
00:14:26,074 --> 00:14:26,341
ACTIVATED.

387
00:14:26,341 --> 00:14:27,742
AND WHAT YOU SEE ON THE RIGHT

388
00:14:27,742 --> 00:14:32,047
HAND SIDE, WE LOOK THE TRANSFER

389
00:14:32,047 --> 00:14:34,115
ACE, BOTH ENZYMES ACTIVATED,

390
00:14:34,115 --> 00:14:35,850
KINASE 1 ACTIVITY IS ALSO

391
00:14:35,850 --> 00:14:38,920
INCREASED AND WE HAVE HERE A

392
00:14:38,920 --> 00:14:40,155
SIGNIFICANT INCREASE IN S1 P

393
00:14:40,155 --> 00:14:43,358
LEVEL IN THE SPINAL CORD TISSUE.

394
00:14:43,358 --> 00:14:45,593
SO NOW USING A VARIETY OF

395
00:14:45,593 --> 00:14:47,395
AGONIST AND ANTAGONIST, WE SAID,

396
00:14:47,395 --> 00:14:48,997
OKAY, CAN WE BLOCK THIS

397
00:14:48,997 --> 00:14:50,632
DEVELOPMENT OF THE PAINFUL

398
00:14:50,632 --> 00:14:52,701
RESPONSE IN RESPONSE TO INJURY?

399
00:14:52,701 --> 00:14:56,137
SO WE USE HERE AT A TIME 1 OF

400
00:14:56,137 --> 00:14:58,807
THE OLD COMPOUNDS, THIS WAS AN

401
00:14:58,807 --> 00:15:00,575
S1 PR3 ANTAGONIST HERE, AND YOU

402
00:15:00,575 --> 00:15:05,747
CAN SEE THAT THE DEVELOPMENT OF

403
00:15:05,747 --> 00:15:07,615
MECHANICAL ALOE DEANIA PAIN IS

404
00:15:07,615 --> 00:15:13,321
NOT AFFECTED BY AN S1 P OR SPR12

405
00:15:13,321 --> 00:15:13,955
ANTAGONIST, VERY MINIMUM CENTER

406
00:15:13,955 --> 00:15:15,256
FOR EXCELLENCE ON AGING EVEN IF

407
00:15:15,256 --> 00:15:18,159
YOU USE THE S1 PR3 ANTAGONIST,

408
00:15:18,159 --> 00:15:18,360
OKAY.

409
00:15:18,360 --> 00:15:20,295
ON THE OTHER HAND WHAT WE FOUND

410
00:15:20,295 --> 00:15:25,867
WAS THAT IF WE USE S1 PR1

411
00:15:25,867 --> 00:15:28,470
ANTAGONIST, THESE ARE A VARIETY

412
00:15:28,470 --> 00:15:29,904
OF FUNCTIONAL AND COMPETITIVE

413
00:15:29,904 --> 00:15:31,840
ANTAGONIST, WE HAD REMARKABLE

414
00:15:31,840 --> 00:15:32,173
EFFECT.

415
00:15:32,173 --> 00:15:34,809
HERE IS AN OLD COMPOUND GIVEN

416
00:15:34,809 --> 00:15:35,944
INTRA FECALLY, THAT MEANS

417
00:15:35,944 --> 00:15:38,513
DIRECTLY OF THE SPINAL CORD OF

418
00:15:38,513 --> 00:15:39,614
RATS THAT UNDERWENT SURGERY AND

419
00:15:39,614 --> 00:15:47,589
IN THIS CASE, WE GIVE THIS

420
00:15:47,589 --> 00:15:48,857
COMPOUND INTERRAFECALLY, AND YOU

421
00:15:48,857 --> 00:15:50,825
CAN SEE THAT THE DEVELOPMENT OF

422
00:15:50,825 --> 00:15:53,294
PAIN RESPONSE IS COMPLETELY

423
00:15:53,294 --> 00:15:53,695
PRESENTED.

424
00:15:53,695 --> 00:15:56,364
WE USE THIS NOVARTIS COMPOUND,

425
00:15:56,364 --> 00:15:59,200
IN THIS CASE WE GIVE IT INTRA

426
00:15:59,200 --> 00:16:00,602
FECALLY AT TIME OF MAXIMUM PAIN

427
00:16:00,602 --> 00:16:02,871
AND WE HAVE A TIME DEPENDENT

428
00:16:02,871 --> 00:16:04,239
REVERSAL OF THAT PAINFUL

429
00:16:04,239 --> 00:16:06,441
RESPONSE, SO WE CAN BLOCK AND WE

430
00:16:06,441 --> 00:16:11,046
CAN PREVENT, WE CAN BLOCK ASK

431
00:16:11,046 --> 00:16:12,080
REVERSE NEUROPATHIC PAIN STATES

432
00:16:12,080 --> 00:16:14,282
AND THE EFFECT THAT WE SEE WITH

433
00:16:14,282 --> 00:16:17,185
THE PHARMACOLOGICAL TOOLS CAN BE

434
00:16:17,185 --> 00:16:20,955
REPLICATED BY GENETIC

435
00:16:20,955 --> 00:16:22,357
MANIPULATIONS, SO THIS IS THE

436
00:16:22,357 --> 00:16:23,625
RESULTS, WE BELIEVE THAT

437
00:16:23,625 --> 00:16:25,160
ACTIVATION, THAT FIRST THE

438
00:16:25,160 --> 00:16:28,229
SYSTEM IS ACTIVATED AND 2, IT

439
00:16:28,229 --> 00:16:29,264
REACTIVATES THE RECEPTOR, IT

440
00:16:29,264 --> 00:16:32,133
CAUSES PAIN AND IF WE CAN

441
00:16:32,133 --> 00:16:33,701
INHIBIT, WE BELIEVE PAINFUL

442
00:16:33,701 --> 00:16:36,237
RESPONSES, OKAY, SO THIS ABOUT

443
00:16:36,237 --> 00:16:38,940
2009, SOME DATA I SHOWED WAS

444
00:16:38,940 --> 00:16:39,707
GENERATED AFTER 2009 BUT THIS IS

445
00:16:39,707 --> 00:16:42,844
WHERE I WAS IN 2009, 2010, THIS

446
00:16:42,844 --> 00:16:44,913
COMES UP THIS REALLY, REALLY

447
00:16:44,913 --> 00:16:52,387
NICE PAPER, WHERE THEY THEY THAT

448
00:16:52,387 --> 00:16:55,290
FING OLIMOD WAS APPROVED FOR THE

449
00:16:55,290 --> 00:16:56,925
TREATMENT OF MULTIPLE SCLEROSIS,

450
00:16:56,925 --> 00:16:59,594
YOU CAN SEE, IT HAD REMARKABLE

451
00:16:59,594 --> 00:17:00,762
SUCCESS FOR MS AND BECAUSE OF

452
00:17:00,762 --> 00:17:02,163
THE SUCCESS A BUNCH OF OTHER

453
00:17:02,163 --> 00:17:05,667
DRUGS HAVE BEEN APPROVED FOR THE

454
00:17:05,667 --> 00:17:07,535
STREEMENT OF MULTIPLE SCLEROSIS.

455
00:17:07,535 --> 00:17:10,472
IN SOME OF THEM ARE MOVING

456
00:17:10,472 --> 00:17:12,740
FORWARD FOR ULRICHRATIVE COLITIS

457
00:17:12,740 --> 00:17:14,976
AS WELL AS SORTING SIGNALS IA

458
00:17:14,976 --> 00:17:17,078
SIS, AND WE ALSO ASKED FOR THE

459
00:17:17,078 --> 00:17:18,179
COMPOUND TO THE PHARMACEUTICAL

460
00:17:18,179 --> 00:17:19,347
COMPANY ANDS THEY DIDN'T GIVE IT

461
00:17:19,347 --> 00:17:20,748
TO US SO WE JUST WENT THROUGH

462
00:17:20,748 --> 00:17:22,183
THE PATENT AND MADE ALL OF THEM

463
00:17:22,183 --> 00:17:23,685
AND TESTED THEM AND SO HAD A

464
00:17:23,685 --> 00:17:25,687
LITTLE BIT OF A BUSY SLIDE, TOOK

465
00:17:25,687 --> 00:17:30,825
MANY YEARS TO GENERATE, AND WHAT

466
00:17:30,825 --> 00:17:32,494
YOU SEE IS THAT DIFFERENT

467
00:17:32,494 --> 00:17:33,528
FUNCTIONAL ANTAGONIST THAT THIS

468
00:17:33,528 --> 00:17:37,398
IS YOUR PAIN RESPONSE AFTER

469
00:17:37,398 --> 00:17:39,634
NERVE INJURY.

470
00:17:39,634 --> 00:17:42,303
WE GIVE IT SPINOMID MORE THAN

471
00:17:42,303 --> 00:17:43,905
ANY OTHER DRUGS AND IN EVERY

472
00:17:43,905 --> 00:17:47,542
SINGLE COMPOUND WE HAVE A VERSAL

473
00:17:47,542 --> 00:17:48,843
THAT ESTABLISHED MECHANICAL ALOE

474
00:17:48,843 --> 00:17:51,613
DEANIA, AND WE DID A LOT OF

475
00:17:51,613 --> 00:17:53,314
STUDIES USING BEHAVIOR, WE

476
00:17:53,314 --> 00:17:55,483
DEMONSTRATED THAT WE HAD

477
00:17:55,483 --> 00:17:56,317
CONDITIONAL PLACE PREFERENCE

478
00:17:56,317 --> 00:17:58,620
ONLY IN INJURED ANIMAL.

479
00:17:58,620 --> 00:18:02,757
WE'VE SHOWN THE EFFECT OF THE

480
00:18:02,757 --> 00:18:03,791
NALOXONE INDEPENDENT, SUGGESTING

481
00:18:03,791 --> 00:18:06,761
THEY'RE NOT ENGAGING AN OPIOID

482
00:18:06,761 --> 00:18:08,363
SYSTEM, AND WE ALSO FOUND NOR

483
00:18:08,363 --> 00:18:10,131
SEX DIFFERENCES ON THE

484
00:18:10,131 --> 00:18:11,065
BEHAVIORIAL PHENOTYPE OR THE

485
00:18:11,065 --> 00:18:11,432
DRUG RESPONSE.

486
00:18:11,432 --> 00:18:13,535
NOW I WILL GIVE YOU 1 EXAMPLE, I

487
00:18:13,535 --> 00:18:15,170
SAID THESE DRUGS ARE FUNCTIONAL

488
00:18:15,170 --> 00:18:16,237
ANTAGONIST AND YOU KNOW WHAT

489
00:18:16,237 --> 00:18:17,772
THAT MEANS, YOU KNOW THIS IS IN

490
00:18:17,772 --> 00:18:22,377
THE CASE OF FTY, FTY NEEDS TO BE

491
00:18:22,377 --> 00:18:25,580
PHOSPHORYLATED FTY AND THEN

492
00:18:25,580 --> 00:18:28,116
BASIC LE, INITIALLY ACTIVATE THE

493
00:18:28,116 --> 00:18:30,285
RECEPTOR AND INTERNALIZED AND

494
00:18:30,285 --> 00:18:31,920
THEN CAUSE A PERMANENT

495
00:18:31,920 --> 00:18:33,188
DEGRADATION OF THE RECEPTOR SO

496
00:18:33,188 --> 00:18:37,091
THERE IS NO SIGNALING OF SPR1 AT

497
00:18:37,091 --> 00:18:38,960
THE CELL SURFACE MEMBRANE, SO

498
00:18:38,960 --> 00:18:40,261
THEY'RE ALL FROM ANTAGONIST, SO

499
00:18:40,261 --> 00:18:43,464
1 OF THE THINGS WE HAD TO

500
00:18:43,464 --> 00:18:46,201
ESTABLISH WAS WE ACTUALLY

501
00:18:46,201 --> 00:18:52,140
LOOKING HERE AT THE S1 P S1 PR1,

502
00:18:52,140 --> 00:18:53,441
ANTAGONISM AND WE DID A LOT OF

503
00:18:53,441 --> 00:18:54,509
TIME AND EXPERIMENTS AND THIS IS

504
00:18:54,509 --> 00:18:55,910
JUST 1 EXPERIMENT I WILL SHOW

505
00:18:55,910 --> 00:18:56,511
YOU.

506
00:18:56,511 --> 00:19:02,717
WE USED THIS HIGHLY SELECTIVE S1

507
00:19:02,717 --> 00:19:05,620
PR1 ANTAGONISM AND DOES IT CAUSE

508
00:19:05,620 --> 00:19:06,621
OR INHIBIT PAIN.

509
00:19:06,621 --> 00:19:14,596
EVERYTHING WE TRIED WITH THIS

510
00:19:14,596 --> 00:19:15,663
HIGHLY CONNECTED AGONIST, THEY

511
00:19:15,663 --> 00:19:17,565
CAUSE SEVERE PAIN, SO WE

512
00:19:17,565 --> 00:19:19,634
EXCLUDED SPR 1 AS A MECHANISM OF

513
00:19:19,634 --> 00:19:23,838
ACTION, AND WE SUBSTANTIATED

514
00:19:23,838 --> 00:19:26,674
THAT BY LOOKING AT A VARIETY OF

515
00:19:26,674 --> 00:19:27,508
COMPETITIVE ANTAGONIST SHOWN ON

516
00:19:27,508 --> 00:19:29,377
THIS SLIDE FOR EXAMPLE, THIS IS

517
00:19:29,377 --> 00:19:31,446
2 COMPOUNDS THAT ARE PURE

518
00:19:31,446 --> 00:19:33,047
ANTAGONIST AND BEHAVE EXACTLY

519
00:19:33,047 --> 00:19:36,117
LIKE THE FUNCTIONAL ANTAGONIST,

520
00:19:36,117 --> 00:19:38,519
BEAUTIFUL REVERSAL OF THAT

521
00:19:38,519 --> 00:19:38,886
RESPONSE.

522
00:19:38,886 --> 00:19:40,121
AND THIS IS JUST A SLIDE THAT

523
00:19:40,121 --> 00:19:42,357
SHOWS SOME OF THE COMPOUNDS THAT

524
00:19:42,357 --> 00:19:44,092
WE'VE TESTED, ALL OF THEM ARE

525
00:19:44,092 --> 00:19:45,960
SELECTED FOR S1 PR1, AND YOU

526
00:19:45,960 --> 00:19:53,701
NOTE THAT SOME OF THE LATER

527
00:19:53,701 --> 00:19:55,603
GENERATIONS SUCH AS OZANIMOD,

528
00:19:55,603 --> 00:19:57,138
THEY DON'T ACT AS THE RECEPTOR

529
00:19:57,138 --> 00:19:59,173
BECAUSE IT WAS THOUGHT THAT WITH

530
00:19:59,173 --> 00:20:03,044
THE CARDIA WITH THE FUNCTIONAL

531
00:20:03,044 --> 00:20:04,879
SP1 R1 ANTAGONIST WAS DUE TO

532
00:20:04,879 --> 00:20:07,782
ACTIVATION OF S1 PR3, SO ALL

533
00:20:07,782 --> 00:20:10,184
PHARMACEUTICAL COMPANIES HAVE

534
00:20:10,184 --> 00:20:11,252
ENGINEERED OUT SPR13 FROM THE

535
00:20:11,252 --> 00:20:13,187
MOLECULE BUT IT TURNS OUT THE

536
00:20:13,187 --> 00:20:15,056
SIDE EFFECT IS MEDIATED BY

537
00:20:15,056 --> 00:20:19,460
ACTIVATION OF S1 PR1.

538
00:20:19,460 --> 00:20:20,762
WE NEXT WANTED TO KNOW WHETHER

539
00:20:20,762 --> 00:20:22,730
THESE COMPOUNDS HAD THE

540
00:20:22,730 --> 00:20:24,399
POTENTIAL TO CAUSE ANALGESIC

541
00:20:24,399 --> 00:20:26,334
TOLERANCE SO HAD IS A SIMPLE

542
00:20:26,334 --> 00:20:28,269
EXPERIMENT DONE WITH A 6 DAY

543
00:20:28,269 --> 00:20:30,238
MINIPUMP EMPLOY WE TAKE THE RAT,

544
00:20:30,238 --> 00:20:34,108
CAUSE NERVE INJURY, PUT THESE

545
00:20:34,108 --> 00:20:37,478
MINIPUMP SUBCUTANEOUSLY AND

546
00:20:37,478 --> 00:20:39,047
DELIVER THE DRUGS SUBCUTANEOUSLY

547
00:20:39,047 --> 00:20:41,849
AND YOU CAN SEE THAT AS WE START

548
00:20:41,849 --> 00:20:43,551
INFUSING, THERE IS REVERSAL OF

549
00:20:43,551 --> 00:20:44,986
THE PAIN RESPONSE WHICH

550
00:20:44,986 --> 00:20:46,187
BASICALLY LASTS UNTIL THE PUMP

551
00:20:46,187 --> 00:20:46,621
DELIVERS THAT DRUG.

552
00:20:46,621 --> 00:20:48,589
IF I WERE TO DO THIS WITH

553
00:20:48,589 --> 00:20:51,059
MORPHINE AFTER 1 DAY, I WOULD

554
00:20:51,059 --> 00:20:54,128
LOSE THE ACTION AND WE'VE

555
00:20:54,128 --> 00:20:56,531
ACTUALLY GONE FURTHER OUT TO 14

556
00:20:56,531 --> 00:20:58,032
DAYS MINIPUMPS AND THEN

557
00:20:58,032 --> 00:20:59,667
EXPERIMENTS BECOME TOO

558
00:20:59,667 --> 00:20:59,934
EXPENSIVE.

559
00:20:59,934 --> 00:21:01,336
ANOTHER QUESTION WE NEEDED TO

560
00:21:01,336 --> 00:21:02,704
ESTABLISH WAS, OKAY, HOW DO

561
00:21:02,704 --> 00:21:04,872
THESE DRUGS COMPARE WITH WHAT IS

562
00:21:04,872 --> 00:21:07,375
USED IN THE CLINIC NOW.

563
00:21:07,375 --> 00:21:10,378
SO THIS A LITTLE BIT COMPLICATED

564
00:21:10,378 --> 00:21:12,080
BUT FOR THE PHARMACOLOGIST WE

565
00:21:12,080 --> 00:21:12,480
WILL GET IT.

566
00:21:12,480 --> 00:21:14,415
SO WHAT WE HAVE HERE ON THE

567
00:21:14,415 --> 00:21:17,685
Y-AXIS IS THE REVERSAL OF PAIN,

568
00:21:17,685 --> 00:21:22,790
AT TIME OF PEAK REVERSAL OF THE

569
00:21:22,790 --> 00:21:22,990
DRUG.

570
00:21:22,990 --> 00:21:27,595
AND WE'VE USED 3 COMMONLY USED

571
00:21:27,595 --> 00:21:29,731
ANALGESIC MORPHIN, GABBA PENTINE

572
00:21:29,731 --> 00:21:32,834
REGIMENIN AND AMTRIP LINE WITH

573
00:21:32,834 --> 00:21:38,072
80/50 OF 8 MICROMOLES FOR AMTRIP

574
00:21:38,072 --> 00:21:40,174
LINE AND 40 FOR GABBA PENTINE

575
00:21:40,174 --> 00:21:41,542
REGIMENIN, BUT IF YOU NOTICE

576
00:21:41,542 --> 00:21:43,745
THEY LOOK AT THE SHIFT TO THE

577
00:21:43,745 --> 00:21:46,214
LEFT IN POTENCY AND EFFICACY OF

578
00:21:46,214 --> 00:21:46,714
THESE COMPOUNDS.

579
00:21:46,714 --> 00:21:49,484
TOTAL SHIFT TO THE LEFT AND WHEN

580
00:21:49,484 --> 00:21:51,652
YOU CAM PAIR THE 50S, YOU CAN

581
00:21:51,652 --> 00:21:55,857
SEE THERE ARE VERY POTENT DRUGS.

582
00:21:55,857 --> 00:21:57,892
MORE OVER WHAT WE DISCOVERIED

583
00:21:57,892 --> 00:22:00,728
WAS THAT THESE COMPOUNDS CAN

584
00:22:00,728 --> 00:22:02,930
ALSO BE GIVEN AS ADJUNCT TO

585
00:22:02,930 --> 00:22:04,332
OPIOIDS AND THIS IS VERY COOL

586
00:22:04,332 --> 00:22:08,703
STORY THAT WAS FUNDED BY NIH

587
00:22:08,703 --> 00:22:09,971
NIDA SEVERAL YEARS AGO MUCH SO

588
00:22:09,971 --> 00:22:11,139
THIS A TYPICAL EXPERIMENT YOU

589
00:22:11,139 --> 00:22:13,007
CAN LOOK FOR THE DEVELOPMENT OF

590
00:22:13,007 --> 00:22:14,609
TOLERANCE, YOU MAKE YOUR INJURY,

591
00:22:14,609 --> 00:22:16,144
THIS IS THE PAIN THAT HAPPENS

592
00:22:16,144 --> 00:22:18,212
AND THEN YOU GIVE IT DAILY,

593
00:22:18,212 --> 00:22:19,947
DAILY INYEKS OF MORPHINE.

594
00:22:19,947 --> 00:22:22,917
AND YOU CAN SEE FIRST DOSE,

595
00:22:22,917 --> 00:22:24,685
BEAUTIFUL REVERSAL, SECOND DOSE,

596
00:22:24,685 --> 00:22:25,953
THIRD DOSE AND OFF YOU GO AND

597
00:22:25,953 --> 00:22:30,792
YOU COME HERE AFTER ABOUT 7, 6

598
00:22:30,792 --> 00:22:32,226
DOSES, MORPHINE LOSES IT'S

599
00:22:32,226 --> 00:22:34,862
ANALGESIC ACTION AND THIS IS A

600
00:22:34,862 --> 00:22:35,496
TOLERANCE.

601
00:22:35,496 --> 00:22:38,499
WELL, WE THEN  DEMONSTRATED WAS

602
00:22:38,499 --> 00:22:39,801
THAT IF YOU TAKE MORPHINE AND

603
00:22:39,801 --> 00:22:43,104
YOU COMBINE IT WITH A VERY LOW

604
00:22:43,104 --> 00:22:47,442
DOSE OF AN SPR1 ANTAGONIST, @

605
00:22:47,442 --> 00:22:50,745
DOSE THAT OUR SUBANALGESIC THAT

606
00:22:50,745 --> 00:22:51,946
CAUSES 5 PERCENT ANNAL GEEZIA

607
00:22:51,946 --> 00:22:54,615
WHEN GIVEN ALOAP, WE BEING

608
00:22:54,615 --> 00:22:57,685
COMPLETELY PROTECT THE LOSS OF

609
00:22:57,685 --> 00:22:59,187
ANALGESIC ACTION TO MORPHINE.

610
00:22:59,187 --> 00:23:00,721
LET'S LOOK AT THE LAST DAY HERE.

611
00:23:00,721 --> 00:23:03,858
THIS A TOTAL LOSS OF MORPHINE

612
00:23:03,858 --> 00:23:06,427
ANALGESIC ACTION AND THIS IS THE

613
00:23:06,427 --> 00:23:09,664
RESPONSE OF MORPHINE WHEN

614
00:23:09,664 --> 00:23:11,766
COMBINED TO 2 OF THE FUNCTIONAL

615
00:23:11,766 --> 00:23:14,535
-- TO S1 PR1 ANTAGONIST.

616
00:23:14,535 --> 00:23:17,872
SO WE BELIEVE THAT THESE ARE S1

617
00:23:17,872 --> 00:23:22,643
PR1 AN TAB TAGANIST, WE

618
00:23:22,643 --> 00:23:23,678
PRESENTED SEVERAL PUBLICATION

619
00:23:23,678 --> 00:23:24,912
HERE.

620
00:23:24,912 --> 00:23:26,514
WE UNDERSTAND MECHANISM OF

621
00:23:26,514 --> 00:23:26,747
ACTION.

622
00:23:26,747 --> 00:23:28,483
I DON'T HAVE TIME TO DELVE INTO

623
00:23:28,483 --> 00:23:30,685
THAT BUT SUFFICE TO SAY, THAT

624
00:23:30,685 --> 00:23:32,920
IT'S A VERY, VERY INTERESTING

625
00:23:32,920 --> 00:23:34,789
STORIES THAT COULD BE PURSUED IN

626
00:23:34,789 --> 00:23:35,723
GOING FORWARD BECAUSE I DON'T

627
00:23:35,723 --> 00:23:37,692
THINK THAT YOU WILL HAVE 1 DRUG

628
00:23:37,692 --> 00:23:40,094
THAT CAN BE EFFECTIVE FOR ALL OF

629
00:23:40,094 --> 00:23:46,467
THE PATIENTS AND SO THE ABILITY

630
00:23:46,467 --> 00:23:48,202
TO DO COMBINATION PHARMACOLOGY

631
00:23:48,202 --> 00:23:50,471
WILL BE VERY IMPORTANT.

632
00:23:50,471 --> 00:23:54,342
JUST TO SAY THAT THE S1 PR1

633
00:23:54,342 --> 00:23:56,978
SYSTEM HAS NO ROLE IN NORMAL

634
00:23:56,978 --> 00:23:58,379
PAIN TRANSMISSION AND THIS IS A

635
00:23:58,379 --> 00:24:03,317
TYPICAL TEST THAT WE DO, I THINK

636
00:24:03,317 --> 00:24:05,152
THIS IS A TAIL FLICK OR HOT

637
00:24:05,152 --> 00:24:07,388
PLATE AND THIS IS THE RESPONSE

638
00:24:07,388 --> 00:24:09,290
TO MORPHINE, SO YOU CAN SEE WE

639
00:24:09,290 --> 00:24:11,392
HAVE A PAIN RELIEF IN THIS TEST

640
00:24:11,392 --> 00:24:14,495
AND THESE DRUGS, THE S1 PR1

641
00:24:14,495 --> 00:24:15,863
ANTAGONIST HAVE NO ACTUAL

642
00:24:15,863 --> 00:24:16,297
RESULT.

643
00:24:16,297 --> 00:24:17,732
THIS IS GOOD BECAUSE PAIN IS

644
00:24:17,732 --> 00:24:19,467
PROTECTIVE AND WE DON'T WANT TO

645
00:24:19,467 --> 00:24:20,668
INTERFERE WITH NORMAL PAIN

646
00:24:20,668 --> 00:24:23,704
SIGNALING, SO THE NEXT QUESTION

647
00:24:23,704 --> 00:24:25,239
WAS, CAN YOU DIRECT ACTIVATION

648
00:24:25,239 --> 00:24:28,042
OF THE S1 PR1 RECEPTOR

649
00:24:28,042 --> 00:24:29,443
RECAPITULATE THE BEHAVIORIAL

650
00:24:29,443 --> 00:24:30,778
PENE PHENOTYPES THAT ARE

651
00:24:30,778 --> 00:24:31,612
ASSOCIATE WIDE NEUROPATHIC PAIN.

652
00:24:31,612 --> 00:24:34,048
SO WE DID THE VERY SIMPLE

653
00:24:34,048 --> 00:24:36,217
SPRPTS, WE USE AGONIST THAT I

654
00:24:36,217 --> 00:24:37,652
MENTIONED TO YOU EARLY, EARLY

655
00:24:37,652 --> 00:24:39,353
ON, WE GAVE IT SPINEALLY, AND

656
00:24:39,353 --> 00:24:42,490
YOU CAN SEE HERE THAT A SINGLE

657
00:24:42,490 --> 00:24:45,660
ADMINISTRATION OF AN SPR1

658
00:24:45,660 --> 00:24:48,529
AGONIST CAUSES SEVERE MECHANICAL

659
00:24:48,529 --> 00:24:53,267
ALLODEANIA, WHICH IS BLOCKED BY

660
00:24:53,267 --> 00:24:53,834
S1 PR1 ANTAGONIST.

661
00:24:53,834 --> 00:24:57,038
SO WE HAD NO IDEA TO POTENTIAL

662
00:24:57,038 --> 00:25:00,942
MECHANISMS WHEREBY ACTIVATION OF

663
00:25:00,942 --> 00:25:02,643
SP1 COULD CAUSE PAIN.

664
00:25:02,643 --> 00:25:03,778
BUT IN THOSE DAYS THERE WAS A

665
00:25:03,778 --> 00:25:05,746
LOT OF DATA THAT WAS COMING OUT

666
00:25:05,746 --> 00:25:08,149
FROM THE FIELD SUGGESTING AN

667
00:25:08,149 --> 00:25:10,785
IMPORTANT ROLE OF TRANSCRIPTION

668
00:25:10,785 --> 00:25:14,188
FACTORS AND MAP KINASES IN

669
00:25:14,188 --> 00:25:15,356
VARIOUS CHRONIC PAIN SETTINGS,

670
00:25:15,356 --> 00:25:20,328
SO WE FELT THAT IT WAS GOOD

671
00:25:20,328 --> 00:25:22,930
STARTING POINT FOR US TO

672
00:25:22,930 --> 00:25:24,932
INVESTIGATE, SO WE'VE LOOKED AT

673
00:25:24,932 --> 00:25:26,367
2 PATHWAYS.

674
00:25:26,367 --> 00:25:30,705
WE LOOKED AT THIS READ SENSITIVE

675
00:25:30,705 --> 00:25:32,306
TRANSCRIPTION FACTOR CALLED

676
00:25:32,306 --> 00:25:34,375
NF-KAPPAB, AS WELL AS MAP KINASE

677
00:25:34,375 --> 00:25:36,711
CALLED P38 AND AT BOTH CASES AT

678
00:25:36,711 --> 00:25:39,780
TIME OF PEAK PAIN WE AWE A

679
00:25:39,780 --> 00:25:43,517
SIGNATURES MIF KABT INCREASE IN

680
00:25:43,517 --> 00:25:45,553
ACTIVATION OF THE NF-KAPPAB

681
00:25:45,553 --> 00:25:47,321
SYSTEM AND ALSO THE MAP KEEN

682
00:25:47,321 --> 00:25:47,488
ACE.

683
00:25:47,488 --> 00:25:49,490
SO THESE DAYS WERE EXCITING

684
00:25:49,490 --> 00:25:51,258
BECAUSE WE KIND OF THEN NEW AND

685
00:25:51,258 --> 00:25:52,760
THIS IS A PROGRESSIVE STORY SO

686
00:25:52,760 --> 00:25:54,228
THIS IS A STORY DURING THE

687
00:25:54,228 --> 00:25:56,097
YEARS, AFTER A COUPLE OF YEARS,

688
00:25:56,097 --> 00:25:57,698
THERE WAS INFORMATION COMING UP

689
00:25:57,698 --> 00:26:00,701
THAT SUGGESTED THAT BOTH P38 AND

690
00:26:00,701 --> 00:26:02,837
NF CAPPA B WERE VERY IMPORTANT

691
00:26:02,837 --> 00:26:06,874
IN ACTIVATION OF THE

692
00:26:06,874 --> 00:26:08,743
INFLAMMASOME, THE NLRP3, AND

693
00:26:08,743 --> 00:26:10,011
NLRP3 AND VERY EXCITING BECAUSE

694
00:26:10,011 --> 00:26:17,151
IT IS THE ENZYME THAT BASIC LE

695
00:26:17,151 --> 00:26:18,419
ACTIVATE CASPACE 1 WHICH CLEANS

696
00:26:18,419 --> 00:26:20,721
AND CONVERTS TO MAKE IL1 BETA.

697
00:26:20,721 --> 00:26:22,490
AND AS I MENTIONED BEFORE

698
00:26:22,490 --> 00:26:25,393
ILBETTA IS A NEW INSIGHTATTORY

699
00:26:25,393 --> 00:26:27,461
CYTOKINE SO I LIKE TO GO AFTER

700
00:26:27,461 --> 00:26:29,497
THIS PROTENTIAL PATHWAY AS A

701
00:26:29,497 --> 00:26:30,231
PROPOSED MODEL.

702
00:26:30,231 --> 00:26:32,600
AND SO WE LOOK AT THE ACTIVATION

703
00:26:32,600 --> 00:26:34,468
OF FINAL AP3 AND AS YOU CAN SEE

704
00:26:34,468 --> 00:26:35,736
ON THE BOTTOM, THE SYSTEM WAS

705
00:26:35,736 --> 00:26:36,537
TURNED ON.

706
00:26:36,537 --> 00:26:41,308
WE SAW AN INCREASE HERE AND

707
00:26:41,308 --> 00:26:43,611
EXPRESSION OF NLRP3, ACTIVATION

708
00:26:43,611 --> 00:26:45,479
OF CASPACE 1 AND INCREASED

709
00:26:45,479 --> 00:26:48,883
PRODUCTION OF IL1 BETA AND SUCH

710
00:26:48,883 --> 00:26:52,586
ACTIVATION WAS BLOCKED BY AT S1

711
00:26:52,586 --> 00:26:53,054
PR1 ANTAGONIST.

712
00:26:53,054 --> 00:26:57,925
SO WE BELIEVE THAT THIS IS

713
00:26:57,925 --> 00:27:00,194
WOPOTENTIAL MECHANISM WHEREBY S1

714
00:27:00,194 --> 00:27:00,628
PR1 INVOLVES PAIN.

715
00:27:00,628 --> 00:27:03,064
SO NOW WE HAVE TO BACK TRACK AND

716
00:27:03,064 --> 00:27:04,465
SAY IS THIS MECHANISM ALSO

717
00:27:04,465 --> 00:27:06,333
INVOLVED IN THE ACTUAL

718
00:27:06,333 --> 00:27:07,234
NEUROPATHIC PAIN STATES SO WE

719
00:27:07,234 --> 00:27:09,937
WENT BACK TO OUR ANIMAL MODEL OF

720
00:27:09,937 --> 00:27:11,005
TRAUMATIC NERVE YOUR AND WHAT WE

721
00:27:11,005 --> 00:27:14,041
DID WAS TO ACTUALLY REMOVE THE

722
00:27:14,041 --> 00:27:16,744
DORSAL HORN OF THE SPINAL CORD 1

723
00:27:16,744 --> 00:27:17,912
HOUR AFTER TREATMENT AND PROCEED

724
00:27:17,912 --> 00:27:19,013
FOR SOME OF THIS PATHWAY AND I

725
00:27:19,013 --> 00:27:20,948
WANT TO SHOW YOU HERE WHAT WE

726
00:27:20,948 --> 00:27:23,184
FOUND AND THIS IS ONLY JUST A

727
00:27:23,184 --> 00:27:24,351
COUPLE OF DATA POINT, THE REST

728
00:27:24,351 --> 00:27:26,921
OF IT IS ALL PUBLISHED AND WHAT

729
00:27:26,921 --> 00:27:29,490
WE FOUND IS THAT IL1 BETA IS

730
00:27:29,490 --> 00:27:31,358
ACTUALLY INCREASED IN RESPONSE

731
00:27:31,358 --> 00:27:33,294
TO TRAUMATIC NERVE INJURY, THAL

732
00:27:33,294 --> 00:27:34,628
HAS ACTUALLY BEEN SHOWN BY MANY

733
00:27:34,628 --> 00:27:35,796
OTHERS BUT WHAT WAS VERY

734
00:27:35,796 --> 00:27:37,098
EXCITING WAS THAT THIS WAS

735
00:27:37,098 --> 00:27:41,702
BLOCKED WHEN WE BLOCKED S1 PR1

736
00:27:41,702 --> 00:27:43,437
EMPLOY BUT WAWE FOUND, WHAT WE

737
00:27:43,437 --> 00:27:45,039
SAW WAS AS IL1 BETA WAS

738
00:27:45,039 --> 00:27:47,041
INCREASED AND WE LOOKED AT IL10,

739
00:27:47,041 --> 00:27:50,411
AS I SAID, IT'S VERY POTENT

740
00:27:50,411 --> 00:27:50,878
INFLAMMATORY CYTOKINE.

741
00:27:50,878 --> 00:27:51,612
SOMETIMES WE FOUND THAT THERE

742
00:27:51,612 --> 00:27:53,914
WAS A SLIGHT INCREASE, SOMETIMES

743
00:27:53,914 --> 00:27:58,018
A SMALL, NO CHANGE, BUT THE REAL

744
00:27:58,018 --> 00:28:01,322
EXCITING PORTION WAS RIGHT HERE;

745
00:28:01,322 --> 00:28:03,290
WAS THIS DRAMATIC INCREASE IN

746
00:28:03,290 --> 00:28:05,493
IL10 PRODUCTION AND SO, WE HAD

747
00:28:05,493 --> 00:28:08,896
NO IDEA WHETHER THIS WAS A FLUKE

748
00:28:08,896 --> 00:28:10,331
THAT TIMES, YOU KNOW CYTOKINES

749
00:28:10,331 --> 00:28:14,135
GO UP AND DOWN ASK THEY HAVE NO

750
00:28:14,135 --> 00:28:14,702
PHARMACOLOGICAL MEANING

751
00:28:14,702 --> 00:28:16,704
WHATSOEVER, AND SO WE WANT TO IS

752
00:28:16,704 --> 00:28:18,372
THIS INCREASE IN IL10

753
00:28:18,372 --> 00:28:19,507
MEANINGFUL, DOES IT CONTRIBUTE

754
00:28:19,507 --> 00:28:24,178
TO THE MODE OF ACTION OF SP1AN

755
00:28:24,178 --> 00:28:25,846
TAGANIST AND TO DO THIS WE'VE

756
00:28:25,846 --> 00:28:26,614
DONE THIS EXPERIMENT.

757
00:28:26,614 --> 00:28:28,849
IT'S A BIT COMPLICATED BUT ALSO

758
00:28:28,849 --> 00:28:30,184
KIND OF EASY.

759
00:28:30,184 --> 00:28:32,486
SO THIS IS A RAT AND WE CAUSE

760
00:28:32,486 --> 00:28:35,489
INJURY, 7 DAYS AFTER WE GO AND

761
00:28:35,489 --> 00:28:38,559
IMPLANT THIS MINIPUMP THAT WILL

762
00:28:38,559 --> 00:28:40,661
DELIVER EITHER NIBR15 OR FTY720.

763
00:28:40,661 --> 00:28:42,429
AND AS I MENTIONED BEFORE THE

764
00:28:42,429 --> 00:28:43,430
UMP YOU PUMPS ARE DELIVERING AND

765
00:28:43,430 --> 00:28:45,699
YOU HAVE THE PAIN RELIEF THAT

766
00:28:45,699 --> 00:28:47,334
LAUGHS UNTIL THE PUMP STOPS

767
00:28:47,334 --> 00:28:51,071
PUMPING AND SO WHAT WE SAID WAS,

768
00:28:51,071 --> 00:28:54,241
IF THIS ANALGESIC ACTION IS

769
00:28:54,241 --> 00:28:59,313
MEDIATED BY THIS INCREASE IN

770
00:28:59,313 --> 00:29:02,349
IL10, WE SHOULD BE TO BLOCK THE

771
00:29:02,349 --> 00:29:04,118
ANALGESIC ACTION AND REVERT IT

772
00:29:04,118 --> 00:29:05,920
BACK TOAIN IF WE TAKE IL10 OUT

773
00:29:05,920 --> 00:29:07,087
FROM THE EQUATION, SO THIS IS

774
00:29:07,087 --> 00:29:10,157
EXACTLY WHAT WE DID, WE GAVE IT

775
00:29:10,157 --> 00:29:11,892
AN INTRA FECAL ADMINISTRATION OF

776
00:29:11,892 --> 00:29:13,394
AN EABT BODY AGAINST IL10 AND

777
00:29:13,394 --> 00:29:16,730
WHAT YOU SEE HAPPENING IS RIGHT

778
00:29:16,730 --> 00:29:17,164
HERE.

779
00:29:17,164 --> 00:29:18,632
THE ANTIBODY WE USE ANALGESIC

780
00:29:18,632 --> 00:29:20,467
ACTION AND YOU CAN DO IT AGAIN

781
00:29:20,467 --> 00:29:21,135
AND AGAIN.

782
00:29:21,135 --> 00:29:24,672
AND THEN WE'VE ALSO USE A IL10

783
00:29:24,672 --> 00:29:27,041
KNOCK OUT ANIMAL, THIS IS THE

784
00:29:27,041 --> 00:29:31,846
RESPONSE OF THE 2 DRUGS, 2

785
00:29:31,846 --> 00:29:33,347
SPR1AN TAGANIST, REVERSAL OF THE

786
00:29:33,347 --> 00:29:34,982
PAIN PAIN RESPONSE AND COMPLETE

787
00:29:34,982 --> 00:29:37,318
LOSS OF THE ANALGESIC ACTION IN

788
00:29:37,318 --> 00:29:39,787
THE KNOCK OUT ANIMAL.

789
00:29:39,787 --> 00:29:42,389
SO WE BELIEVE THAT IL10 IS ALSO

790
00:29:42,389 --> 00:29:44,558
CRITICAL OF THE MECHANISM OF

791
00:29:44,558 --> 00:29:49,330
ACTION OF THESE DRUGS.

792
00:29:49,330 --> 00:29:53,100
SO IF WE MOVE, IF WE WANT TO

793
00:29:53,100 --> 00:29:56,804
CONSIDER S1 PR1 AS A POTENTIAL

794
00:29:56,804 --> 00:29:58,606
TARGET FOR DIFFERENT TYPES OF

795
00:29:58,606 --> 00:30:00,174
NEUROPATHIC PAIN, YOU HAVE TO

796
00:30:00,174 --> 00:30:03,043
TEST THE MOLECULES AND THE

797
00:30:03,043 --> 00:30:05,212
HYPOTHESIS, IN A VARIETY OF

798
00:30:05,212 --> 00:30:08,549
SETTINGS SO THAT YOU CAN THEN --

799
00:30:08,549 --> 00:30:09,850
SO THAT HOPEFULLY YOU CAN THEN

800
00:30:09,850 --> 00:30:11,585
CHOOSE WHAT THE BEST CLINICAL

801
00:30:11,585 --> 00:30:16,590
POPULATION IS GOING TO BE AND 1

802
00:30:16,590 --> 00:30:19,059
OF THE RESEARCH AREA, IN MY

803
00:30:19,059 --> 00:30:21,996
LABORATORY THAT IS VERY, VERY

804
00:30:21,996 --> 00:30:26,233
INTERESTED IN, IS CHEMO THERAPY

805
00:30:26,233 --> 00:30:29,270
INDUCED NEUROPATHIC PAIN, SO

806
00:30:29,270 --> 00:30:30,871
CHEMO THERAPY INDUCED PAIN IS 1

807
00:30:30,871 --> 00:30:32,907
OF THE TOXICITIES OF WIDELY USED

808
00:30:32,907 --> 00:30:35,809
THERAPEUTICS THAT HAVE

809
00:30:35,809 --> 00:30:40,748
DRASTICALLY DIFFERENT MECHANISM,

810
00:30:40,748 --> 00:30:44,718
IT HAPPENS WITH THE DRUGS, WITH

811
00:30:44,718 --> 00:30:48,389
PLATINUM BASED DRUGS, VINCA

812
00:30:48,389 --> 00:30:49,523
ALKALOIDS, PROTEIN COMPLEXIOSOME

813
00:30:49,523 --> 00:30:51,358
INHIBITORS AND OTHER NEW

814
00:30:51,358 --> 00:30:51,625
BIOLOGICS.

815
00:30:51,625 --> 00:30:53,294
IT IMPACTS THE TREATMENT OF

816
00:30:53,294 --> 00:30:56,630
CANCER PATES BUT IT ALSO HAS A

817
00:30:56,630 --> 00:30:57,798
MAJOR IMPACT FOR THE QUALITY OF

818
00:30:57,798 --> 00:31:02,403
LIFE FOR THE CANCER SURVIVORS.

819
00:31:02,403 --> 00:31:05,172
AND BY 2040 WE'RE EXPECTING

820
00:31:05,172 --> 00:31:06,407
26 MILLION CANCER SURVIVORS SO

821
00:31:06,407 --> 00:31:08,475
ADDRESSING THIS IS OF MAJOR

822
00:31:08,475 --> 00:31:11,145
IMPORTANCE AND THERE ARE NO

823
00:31:11,145 --> 00:31:11,512
APPROVED DRUGS.

824
00:31:11,512 --> 00:31:14,615
SO, AS I SAID, WE'VE SPENT MANY

825
00:31:14,615 --> 00:31:16,383
YEARS LOOKING AT CIPN, WE HAVE

826
00:31:16,383 --> 00:31:17,618
ALL OF THE ANIMAL MODELS IN THE

827
00:31:17,618 --> 00:31:21,255
LAB AND I WILL JUST GIVE YOU A

828
00:31:21,255 --> 00:31:23,390
LITTLE EXAMPLE OF SOME OF THE

829
00:31:23,390 --> 00:31:25,025
ROLE OF S1 P THAT IS VERY

830
00:31:25,025 --> 00:31:27,428
CONSISTENT TO WHAT WE ALSO SEE

831
00:31:27,428 --> 00:31:30,831
IN TRAUMATIC NERVE INJURY

832
00:31:30,831 --> 00:31:31,065
MODELS.

833
00:31:31,065 --> 00:31:36,337
SO THIS IS AN EXAMPLE OF P A

834
00:31:36,337 --> 00:31:38,672
CLITAXEL, WIDELY USED FOR BREAST

835
00:31:38,672 --> 00:31:41,108
CANCER, WE USE IT IN RATS, WELL

836
00:31:41,108 --> 00:31:42,443
DEFINED DOSE IN NAIVE ANIMALS

837
00:31:42,443 --> 00:31:46,981
AND WE CAN TALK ABOUT TUMOR

838
00:31:46,981 --> 00:31:47,681
BEARING ANIMALS LATER.

839
00:31:47,681 --> 00:31:50,384
BUT WHAT YOU SEE IS THAT AFTER

840
00:31:50,384 --> 00:31:53,287
THE FIRST ROUND OF P A CLITAXEL,

841
00:31:53,287 --> 00:31:55,956
IF YOU MONITOR THE DEVELOPMENT

842
00:31:55,956 --> 00:31:58,525
OF PAIN, METRICS MECHANICAL ALOE

843
00:31:58,525 --> 00:31:59,426
DEANIA, YOU HAVE SIGNIFICANT

844
00:31:59,426 --> 00:32:01,161
DEVELOP AM OF THAT ALOE DEANIC

845
00:32:01,161 --> 00:32:01,528
RESPONSE.

846
00:32:01,528 --> 00:32:02,830
ON SO THIS IS PROBABLY WHAT IT

847
00:32:02,830 --> 00:32:04,565
LOOKS LIKE WHEN THE PATIENT

848
00:32:04,565 --> 00:32:05,733
RECEIVES THESE DRUGS AND THEY

849
00:32:05,733 --> 00:32:08,035
PUT THE SHIRT ON, JUST THE TOUCH

850
00:32:08,035 --> 00:32:10,104
ON THE SKIN CAUSES PAIN SO THIS

851
00:32:10,104 --> 00:32:12,973
IS DEFINED AS ALOE DEANIA.

852
00:32:12,973 --> 00:32:16,076
SO WE REMOVE HERE THE DORSAL

853
00:32:16,076 --> 00:32:18,112
PART OF THE SPINAL CORD AND WE

854
00:32:18,112 --> 00:32:19,413
PROBE FOR THE ACTIVATION OF

855
00:32:19,413 --> 00:32:29,923
THESE ENZYMES AND AS I SHOWED

856
00:32:47,207 --> 00:32:48,275
YOU BEFORE -- SERIES POINTS MID

857
00:32:48,275 --> 00:32:52,413
IS 1 OF THE MOST POTENT PRO

858
00:32:52,413 --> 00:32:53,347
APOPTOTIC MEDIATOR.

859
00:32:53,347 --> 00:32:55,983
TURNS OUT THAT S1 P IS A VERY

860
00:32:55,983 --> 00:32:57,084
APPROPRIATE MEDIATOR SO THIS I

861
00:32:57,084 --> 00:32:58,519
DIDN'T THINK AND YANG OF SERIES

862
00:32:58,519 --> 00:33:00,354
POINTS MID IN S1 P, SO IN FACT

863
00:33:00,354 --> 00:33:02,389
PEOPLE ARE GOING AFTER S1 P, AND

864
00:33:02,389 --> 00:33:05,325
IN THE S1 P ARE RECEPTOR AS A

865
00:33:05,325 --> 00:33:06,827
NOVEL ANTICANCER TYPE OF

866
00:33:06,827 --> 00:33:07,161
APPROACH.

867
00:33:07,161 --> 00:33:11,632
SO THE SYSTEM IS TURNED ON, IN

868
00:33:11,632 --> 00:33:12,966
THESE MODELS AND CONSISTENT TO

869
00:33:12,966 --> 00:33:18,138
OTHER MODELS OF TRAUMATIC NERVE

870
00:33:18,138 --> 00:33:20,841
INJURY, CHEMO THERAPEUTICS

871
00:33:20,841 --> 00:33:21,909
ACTIVATE REDOX SENSITIVE

872
00:33:21,909 --> 00:33:23,677
TRANSCRIPTION FACTORS AND MAP

873
00:33:23,677 --> 00:33:26,980
KINASES, AND HERE I SHOW

874
00:33:26,980 --> 00:33:28,148
NF-KAPPAB AND P65, HERE I GIVE

875
00:33:28,148 --> 00:33:31,819
YOU AN EXAMPLE OF ERK WHICH IS

876
00:33:31,819 --> 00:33:34,021
ANOTHER MAP KINASE AND IT'S

877
00:33:34,021 --> 00:33:35,222
INCREASED AND ACTIVATION OF P38

878
00:33:35,222 --> 00:33:39,793
AND WE KNOW THAT THESE SIGNALING

879
00:33:39,793 --> 00:33:40,461
PATHWAYS ARE PHARMAICOLOGICALLY

880
00:33:40,461 --> 00:33:41,428
IMPORTANT BECAUSE IF WE BLOCK

881
00:33:41,428 --> 00:33:43,964
THEM WE CAN ALSO PREVENT

882
00:33:43,964 --> 00:33:46,733
DEVELOPMENT OF ALLODYNIA SO THEY

883
00:33:46,733 --> 00:33:47,367
ARE MEANINGFUL.

884
00:33:47,367 --> 00:33:48,969
OKAY, SO THIS IS ACTUALLY --

885
00:33:48,969 --> 00:33:51,505
THIS PAPER WAS PUBLISHED IN

886
00:33:51,505 --> 00:33:55,909
2014, THIS EXPERIMENT WAS

887
00:33:55,909 --> 00:33:57,277
ACTUALLY GENERATED IN 2010.

888
00:33:57,277 --> 00:33:58,812
SO ABOUT 4 YEARS TO WRAP OUR

889
00:33:58,812 --> 00:34:00,180
HEAD AROUND ALL OF THIS.

890
00:34:00,180 --> 00:34:04,284
THIS WAS 1 OF THE VERY OLD FIRST

891
00:34:04,284 --> 00:34:06,820
COMPETITIVE S1 PR1 ANTAGONIST

892
00:34:06,820 --> 00:34:08,555
CALLED W146, IT'S A DIRTY

893
00:34:08,555 --> 00:34:09,590
COMPOUND, WE DIDN'T KNOW HOW

894
00:34:09,590 --> 00:34:11,725
LONG TO TREAT THE ANIMALS FOR SO

895
00:34:11,725 --> 00:34:14,928
WE DECIDED WE WOULD TREAT FOR 16

896
00:34:14,928 --> 00:34:15,462
DAYS.

897
00:34:15,462 --> 00:34:17,097
THE COMPOUNDS WERE GIVEN INTRA

898
00:34:17,097 --> 00:34:18,398
FECALLY AND YOU CAN SEE HERE

899
00:34:18,398 --> 00:34:21,702
THAT BASICALLY IF WE BLOCK S1

900
00:34:21,702 --> 00:34:22,936
PR1, WE PREVENT THE BIRTH OF

901
00:34:22,936 --> 00:34:25,272
ALEE DEAN RAW DATA AND HYPER

902
00:34:25,272 --> 00:34:28,675
ANNAL GEEZIA IN A DOZE DEPENDENT

903
00:34:28,675 --> 00:34:29,743
MANNER AND MECHANISM BY WHICH

904
00:34:29,743 --> 00:34:31,912
THIS HAPPENS AS I MENTION IN THE

905
00:34:31,912 --> 00:34:35,549
PREVIOUS MODEL IS BY BLOCKING

906
00:34:35,549 --> 00:34:36,049
NF-KAPPAB.

907
00:34:36,049 --> 00:34:37,651
AS YOU SEE WE PLOK IT AND MAP

908
00:34:37,651 --> 00:34:39,419
KINASES AND WHEN WE LOOK AT

909
00:34:39,419 --> 00:34:41,488
CYTOKEENS AGAIN AND CONSISTENTLY

910
00:34:41,488 --> 00:34:46,493
WE ALSO BLOCK AND ATTENUATE

911
00:34:46,493 --> 00:34:47,895
THESE PROINFLAMM -ATORY BETA,

912
00:34:47,895 --> 00:34:50,264
IL10 AND WHEN WE LOOK AT IL10 IS

913
00:34:50,264 --> 00:34:52,499
INCREASES, THIS IS INCREASINGLY

914
00:34:52,499 --> 00:34:53,700
RESULTS, IL4 IS INCREASED WE

915
00:34:53,700 --> 00:34:54,968
HAVEN'T DONE EXPERIMENTS THAT

916
00:34:54,968 --> 00:34:56,537
WE'VE DONE FOR IL10 BUT IN THE

917
00:34:56,537 --> 00:35:00,507
FUTURE, IT COULD BE SOMETHING

918
00:35:00,507 --> 00:35:01,808
INTERESTING TO PURSUE.

919
00:35:01,808 --> 00:35:04,244
SO MORE RECENTLY, WE SAID, OKAY,

920
00:35:04,244 --> 00:35:06,680
WHAT HAPPENS IF WE GIVE THE DRUG

921
00:35:06,680 --> 00:35:08,549
ONLY, SO WE HAVE THE NEWER DRUGS

922
00:35:08,549 --> 00:35:10,484
THAT CAME TO MARKET, SO WE

923
00:35:10,484 --> 00:35:12,886
SCREEN THEM AND WE SAID CAN WE

924
00:35:12,886 --> 00:35:14,621
BLOCK THE DEVELOPMENT OF

925
00:35:14,621 --> 00:35:16,056
NEUROPATHIC PAIN BY GIVING AND

926
00:35:16,056 --> 00:35:18,225
RESTRICTING THE USE OF THESE

927
00:35:18,225 --> 00:35:22,663
ANTAGONIST ONLY WHEN THE RAT

928
00:35:22,663 --> 00:35:24,097
SEES THE CHEMO THERAPEUTICS.

929
00:35:24,097 --> 00:35:28,235
BECAUSE WHEN YOU LOOK AT THESE

930
00:35:28,235 --> 00:35:29,203
PAINFUL ASSOCIATION WITH

931
00:35:29,203 --> 00:35:30,137
NEUROPATHIC PAIN, IT'S PROBABLY

932
00:35:30,137 --> 00:35:31,171
THE ONLY ASSOCIATION WHERE YOU

933
00:35:31,171 --> 00:35:32,673
CAN GO IN AND GIVE THAT DRUG

934
00:35:32,673 --> 00:35:35,008
WHEN THE PATIENT SEES THE CHEMO

935
00:35:35,008 --> 00:35:36,076
THERAPEUTIC, ALL THE OTHER

936
00:35:36,076 --> 00:35:38,612
INSTANCES YOU WANT DRUGS THAT

937
00:35:38,612 --> 00:35:40,013
WORK THERAPEUTICALLY BUT HERE WE

938
00:35:40,013 --> 00:35:42,249
HAVE THE OPTION OF WORKING

939
00:35:42,249 --> 00:35:43,350
PROPHYLACTICALLY AS WELL AS

940
00:35:43,350 --> 00:35:45,986
THERAPEUTICALLY AND THIS WAS

941
00:35:45,986 --> 00:35:47,588
REALLY ASTONISHING, ONLY WHEN WE

942
00:35:47,588 --> 00:35:49,656
RESTRICTED THE CHEEM OR

943
00:35:49,656 --> 00:35:51,725
THERAPEUTIC WITH -- CHEMO

944
00:35:51,725 --> 00:35:57,297
THERAPEUTIC WITH THE SP1 R1 AN

945
00:35:57,297 --> 00:35:58,765
TANANIST, COMPLETELY PREVENTED

946
00:35:58,765 --> 00:36:00,167
THE DEVELOPMENT OF NEUROPATHIC

947
00:36:00,167 --> 00:36:01,101
PAIN.

948
00:36:01,101 --> 00:36:04,638
SO THE MECHANISM UNDERLYING THIS

949
00:36:04,638 --> 00:36:05,672
DISEASE PHENOTYPE BUT DON'T

950
00:36:05,672 --> 00:36:07,207
UNDERSTAND BUT WE HAVE REALLY

951
00:36:07,207 --> 00:36:10,210
EXCITING DATA FROM THE SINGLE

952
00:36:10,210 --> 00:36:11,511
CELL RNASEQ DATA AND WE

953
00:36:11,511 --> 00:36:12,346
SUBMITTED THE PAPER YESTERDAY TO

954
00:36:12,346 --> 00:36:15,449
PAIN AND I DON'T HAVE TIME TO --

955
00:36:15,449 --> 00:36:18,452
WE CAN TALK LATER ABOUT THAT.

956
00:36:18,452 --> 00:36:21,622
WE'VE TESTED MANY COMPOUNDS,

957
00:36:21,622 --> 00:36:24,358
WE'VE OBTAINED SIMILAR

958
00:36:24,358 --> 00:36:26,226
EXPERIMENTS, RESULTS WITHOUT THE

959
00:36:26,226 --> 00:36:27,027
CHEMO THERAPEUTICS AND

960
00:36:27,027 --> 00:36:28,962
EXPERIMENTS IN TUMOR BEARS MICE

961
00:36:28,962 --> 00:36:29,930
ARE ONGOING IN PROGRESS.

962
00:36:29,930 --> 00:36:33,867
I CAN JUST TELL YOU THAT THE

963
00:36:33,867 --> 00:36:35,936
DRUG WORKS IN TUMOR BEARING MICE

964
00:36:35,936 --> 00:36:37,104
THAT ALSO PREVENT THE TUMOR

965
00:36:37,104 --> 00:36:40,907
GROWTH AS SHOWN BY OTHERS, AND

966
00:36:40,907 --> 00:36:43,343
THE PRESENCE OF THE TUMOR ITSELF

967
00:36:43,343 --> 00:36:47,147
DOES NOT MAKE THE PAINFUL

968
00:36:47,147 --> 00:36:47,814
PHENOTYPE WORSE.

969
00:36:47,814 --> 00:36:51,018
BUT THERE'S A VERY COMPLICATED

970
00:36:51,018 --> 00:36:52,286
EXPERIMENTS, IN WORKING WITH 1

971
00:36:52,286 --> 00:36:53,820
YEAR AND WE STILL ARE NOT DONE

972
00:36:53,820 --> 00:36:57,591
WITH IT, BUT WE ARE DOING --

973
00:36:57,591 --> 00:37:00,193
WE'RE MAKING PROGRESS, SO, THEY

974
00:37:00,193 --> 00:37:02,262
NOT ONLY CAN BLOCK IT BUT THEY

975
00:37:02,262 --> 00:37:05,198
CAN ALSO PREVENT IT, THIS IS AN

976
00:37:05,198 --> 00:37:10,270
EXPERIMENT DONE ON DAY 16 WHEN

977
00:37:10,270 --> 00:37:12,639
YOU HAVE MAXIMUM PAIN WE FUSE IN

978
00:37:12,639 --> 00:37:14,875
THE LIVER 3 DIFFERENT KIND OF

979
00:37:14,875 --> 00:37:16,410
COMPOUNDS SHOWN HERE AND IN ALL

980
00:37:16,410 --> 00:37:19,513
INSTANCES WE CAN REVERSE THAT

981
00:37:19,513 --> 00:37:20,314
PAINFUL PHENOTYPE.

982
00:37:20,314 --> 00:37:21,815
THIS IS BEAUTIFUL BUT IF YOU CAN

983
00:37:21,815 --> 00:37:23,317
JUST LOOK AT THE ACTIVATION OF

984
00:37:23,317 --> 00:37:27,020
THESE, ALL OF THESE PATHWAYS AND

985
00:37:27,020 --> 00:37:29,323
ALL THESE SPHINGOLIPIDS THEY ARE

986
00:37:29,323 --> 00:37:31,425
INCREASED IN RESPONSE TO SIMPLE

987
00:37:31,425 --> 00:37:32,326
CHEEM OR THERAPEUTIC.

988
00:37:32,326 --> 00:37:34,528
AS I MENTIONED WHAT IS EXCITING

989
00:37:34,528 --> 00:37:38,165
HERE IS THAT THE S1 PR1

990
00:37:38,165 --> 00:37:40,834
ANTAGONIST ARE MOVING FORWARD AS

991
00:37:40,834 --> 00:37:42,636
ANTICANCER DRUGS SO WE MAY HAVE

992
00:37:42,636 --> 00:37:45,405
AN OPPORTUNITY WHERE WE MIGHT

993
00:37:45,405 --> 00:37:46,373
PREVENT NEUROTOXICITY AND ALSO

994
00:37:46,373 --> 00:37:48,008
ADDRESS THE TUMOR BURDEN ITSELF.

995
00:37:48,008 --> 00:37:51,611
ALL RIGHT, SO THEN NEXT QUESTION

996
00:37:51,611 --> 00:37:54,781
WAS, WHAT IS THE CELLULAR

997
00:37:54,781 --> 00:37:56,416
SUBSTRATE FOR SP1 R1 ACTIVITY?

998
00:37:56,416 --> 00:37:59,319
SO YOU REMEMBER AT THE BEGINNING

999
00:37:59,319 --> 00:38:03,056
THAT SP1 R1 IS HIGHLY EXPRESSED

1000
00:38:03,056 --> 00:38:05,025
ON THE ASTROCYTES IN HUMANS AND

1001
00:38:05,025 --> 00:38:07,994
IN RODENTS BUT ALSO IT'S

1002
00:38:07,994 --> 00:38:10,864
DRASTICALLY INCREASED IN THE

1003
00:38:10,864 --> 00:38:11,531
ASTRO SITTIC POPULATION.

1004
00:38:11,531 --> 00:38:14,034
WE FOUND THAT IN MODELS OF

1005
00:38:14,034 --> 00:38:16,103
NEUROPATHIC PAIN BUT A LOT OF

1006
00:38:16,103 --> 00:38:18,972
THIS DATA WAS ACTUALLY -- WAS

1007
00:38:18,972 --> 00:38:23,143
ACTUALLY GATHERED AT A TIME BY

1008
00:38:23,143 --> 00:38:26,646
WONDERFUL WORK BY GERALD SHUN

1009
00:38:26,646 --> 00:38:32,219
CHOI AT THE SCIPTSWHERE HE

1010
00:38:32,219 --> 00:38:34,821
SHOWED THAT ASTRO SIGHTS ARE

1011
00:38:34,821 --> 00:38:38,125
AFFECTED BY THESE SP1 R1

1012
00:38:38,125 --> 00:38:39,493
ANTAGONIST AND THEY CONTRIBUTE

1013
00:38:39,493 --> 00:38:42,362
TO THE DEVELOPMENT OF MULTIPLE

1014
00:38:42,362 --> 00:38:42,896
SCLEROSIS.

1015
00:38:42,896 --> 00:38:44,264
SO PUTTING HIS DATA TOGETHER AND

1016
00:38:44,264 --> 00:38:45,932
OUR DATA TOGETHER, WE STARTED A

1017
00:38:45,932 --> 00:38:48,201
COLLABORATION AND SAID, WELL,

1018
00:38:48,201 --> 00:38:49,603
YOU KNOW, IF THAT'S THE

1019
00:38:49,603 --> 00:38:56,143
MECHANISM OF ACTION IN MULTIPLE

1020
00:38:56,143 --> 00:38:58,145
SCLEROSIS AND S1 PR1 IS IN THE

1021
00:38:58,145 --> 00:38:59,980
ASTRO SIGHT MAYBE WE SHOULD HAVE

1022
00:38:59,980 --> 00:39:01,248
SIMILAR EFFECT.

1023
00:39:01,248 --> 00:39:02,682
THIS WAS OUR HYPOTHESIS.

1024
00:39:02,682 --> 00:39:04,084
WE COLLABORATED AND HE SENT US

1025
00:39:04,084 --> 00:39:05,285
HIS MICE AND SO WHAT YOU SEE

1026
00:39:05,285 --> 00:39:07,254
HERE AND ALL OF THIS DATA IS

1027
00:39:07,254 --> 00:39:12,025
PUBLISHED SO THIS IS OUR ASTRO

1028
00:39:12,025 --> 00:39:12,926
SIGHTIC SPECIFIC SPR1 KNOCKOUT

1029
00:39:12,926 --> 00:39:13,293
MICE.

1030
00:39:13,293 --> 00:39:14,294
WE'VE DONE MANY, MANY TESTS AND

1031
00:39:14,294 --> 00:39:17,063
THE BOTTOM LINE IS I DID NOT

1032
00:39:17,063 --> 00:39:19,499
DEVELOP ALLODYNIA IN RESPONSE TO

1033
00:39:19,499 --> 00:39:21,701
S1 PR1 ACTIVATION, THIS IS THE

1034
00:39:21,701 --> 00:39:24,571
WILD-TYPE, THIS IS WHERE WE GIVE

1035
00:39:24,571 --> 00:39:26,973
INTRA FECAL ADMINISTRATION OF

1036
00:39:26,973 --> 00:39:28,275
THE WILD-TYPE, NOTHING HAPPENS

1037
00:39:28,275 --> 00:39:30,444
IN THE KNOCK OUT, THIS IS A

1038
00:39:30,444 --> 00:39:31,845
MODEL OF TRAUMATIC NERVE INJURY,

1039
00:39:31,845 --> 00:39:33,146
THIS IS THE RESPONSE IN THE

1040
00:39:33,146 --> 00:39:35,115
WILD-TYPE, YOU HAVE THE PAINFUL

1041
00:39:35,115 --> 00:39:35,782
RESPONSE, NOTHING HAPPENS IN A

1042
00:39:35,782 --> 00:39:39,886
KNOCK OUT AND THIS IS WITH THE

1043
00:39:39,886 --> 00:39:41,288
DISEASE IN THE WILD-TYPE AND

1044
00:39:41,288 --> 00:39:42,823
THIS IS THE KNOCK OUT.

1045
00:39:42,823 --> 00:39:44,724
ALL OF IT IS PUBLISHED, OKAY, SO

1046
00:39:44,724 --> 00:39:47,160
WHEN WE LOOK AT THE RESULTS,

1047
00:39:47,160 --> 00:39:49,329
THEN IN THE ASTRO SIGHT SPECIFIC

1048
00:39:49,329 --> 00:39:50,831
KNOCK DOWN MICE, WE FOUND WHAT

1049
00:39:50,831 --> 00:39:52,999
HE ALSO HAS FOUND IN THE MODELS

1050
00:39:52,999 --> 00:39:54,067
OF THE MULTIPLE SCLEROSIS AND

1051
00:39:54,067 --> 00:39:56,736
THAT IS THAT WE LOSE THE

1052
00:39:56,736 --> 00:39:59,039
PHARMAICOLOGICAL ACTION OF THESE

1053
00:39:59,039 --> 00:39:59,372
DRUGS.

1054
00:39:59,372 --> 00:40:00,073
SOPHISTICATEDY THIS IS AN

1055
00:40:00,073 --> 00:40:05,579
EXAMPLE IN THE TRAUMATIC NERVE

1056
00:40:05,579 --> 00:40:16,122
INJURY, AND THIS IS BORTEZOMIB,

1057
00:40:19,125 --> 00:40:23,096
SAME THING IN THE BORTEZOMIB, SO

1058
00:40:23,096 --> 00:40:25,232
WE BELIEVE THIS WAS PUBLISHED

1059
00:40:25,232 --> 00:40:28,301
AND ASTRO SIGHTS CONTRIBUTE TO

1060
00:40:28,301 --> 00:40:29,369
SP1 R1 NEUROPATHIC PAIN STATES

1061
00:40:29,369 --> 00:40:32,472
AND THEY'RE ALSO TARGET FOR

1062
00:40:32,472 --> 00:40:33,406
PHARMAICOLOGICAL ACTION, AND WE

1063
00:40:33,406 --> 00:40:34,774
REALLY KIND OF LIKE THIS,

1064
00:40:34,774 --> 00:40:37,744
BECAUSE WE HAVE NOW 1 CELL TYPE

1065
00:40:37,744 --> 00:40:41,481
THAT CAN RESPOND TO THAT DRUG.

1066
00:40:41,481 --> 00:40:43,383
SO THIS IS A WORKING HYPOTHESIS

1067
00:40:43,383 --> 00:40:48,388
THAT WE BUILD OVER THE LAST 14

1068
00:40:48,388 --> 00:40:50,490
YEARS, LITTLE BY LITTLE FOR

1069
00:40:50,490 --> 00:40:51,892
CHEMO THERAPY INCREASES S1 P

1070
00:40:51,892 --> 00:40:54,294
WHICH THEN ACTIVATE THE

1071
00:40:54,294 --> 00:40:59,032
RECEPTOR, TURNS ON P38 AND

1072
00:40:59,032 --> 00:41:00,800
ACTIVATES THE INFLAMMASOME, IL1

1073
00:41:00,800 --> 00:41:02,836
BETA IS RELEASED, THIS IS A

1074
00:41:02,836 --> 00:41:06,139
SLIDE MADE VERY, VERY SIMPLE,

1075
00:41:06,139 --> 00:41:10,577
AND THEN IL1 BETA CAN INCREASE

1076
00:41:10,577 --> 00:41:11,978
NEURONAL ACCESSIBILITY BY

1077
00:41:11,978 --> 00:41:13,146
PRESYNAPTICALLY OR POST

1078
00:41:13,146 --> 00:41:14,848
SYNAPTICALLY BUT IT WAS VERY

1079
00:41:14,848 --> 00:41:17,083
SIMPLE BECAUSE IERK L1 BETA CAN

1080
00:41:17,083 --> 00:41:17,784
ACTIVATE SURROUNDING DPLEEL

1081
00:41:17,784 --> 00:41:18,752
CELLS AND SO FORTH BUT WE ALSO

1082
00:41:18,752 --> 00:41:22,022
KNOW FROM THE LITERATURE AND

1083
00:41:22,022 --> 00:41:23,757
WE'VE ALSO DONE EXPERIMENTS THAT

1084
00:41:23,757 --> 00:41:26,226
IL1 BETA BY ACTIVATING ON GLIAL

1085
00:41:26,226 --> 00:41:28,094
CELLS CAN ACTUALLY DAMPEN IL10.

1086
00:41:28,094 --> 00:41:32,632
SO THERE WAS LESS IL10 THAT WAS

1087
00:41:32,632 --> 00:41:32,933
RELEASED.

1088
00:41:32,933 --> 00:41:34,267
AS I MENTIONED THIS IS VERY

1089
00:41:34,267 --> 00:41:35,702
COMPLICATED AND WE KNOW IT'S NOT

1090
00:41:35,702 --> 00:41:37,103
ONLY ABOUT THE ASTROCYTE BECAUSE

1091
00:41:37,103 --> 00:41:39,439
THERE'S COMMUNICATION WITH THE

1092
00:41:39,439 --> 00:41:42,242
INFILTRATING T-CELLS WITH

1093
00:41:42,242 --> 00:41:47,914
MICROGLIA AND OTHER CYTOKINE --

1094
00:41:47,914 --> 00:41:48,548
OTHER DPLEEL CELLS.

1095
00:41:48,548 --> 00:41:50,784
SO WHEN WE BLOCK THE RECEPTOR,

1096
00:41:50,784 --> 00:41:54,087
WE THEN INHIBIT BASICALLY THE

1097
00:41:54,087 --> 00:41:55,956
INFLAMMASOME, WE REDUCE LEFT

1098
00:41:55,956 --> 00:41:58,091
SIDE IL1 BETA TO BE RELEASED AND

1099
00:41:58,091 --> 00:41:59,526
NOW IL1 BETA THE BREAK, WE TAKE

1100
00:41:59,526 --> 00:42:02,062
OFF THE BREAK THAT ILBETTA 1 HAS

1101
00:42:02,062 --> 00:42:04,598
ON IL10 AND WE HAVE MORE IL10

1102
00:42:04,598 --> 00:42:07,701
COMING OUT AND THEN IL10 CAN

1103
00:42:07,701 --> 00:42:09,402
DAMPEN NEURONAL EXCITABILITY BY

1104
00:42:09,402 --> 00:42:10,270
SEVERAL MECHANISM, 1 ILLUSTRATED

1105
00:42:10,270 --> 00:42:13,173
HERE IS BY ACTIVATING THE

1106
00:42:13,173 --> 00:42:15,709
RECEPTOROT PRESYNAPTIC NERVE

1107
00:42:15,709 --> 00:42:15,976
TERMINAL.

1108
00:42:15,976 --> 00:42:16,910
NEXT QUESTION, THIS IS SOMETHING

1109
00:42:16,910 --> 00:42:19,613
WE ARE WORKING ON HERE, OKAY, SO

1110
00:42:19,613 --> 00:42:21,982
WHAT TRIGGERS THE ENHANCED

1111
00:42:21,982 --> 00:42:25,352
PRODUCTION OF THESE SINGLE

1112
00:42:25,352 --> 00:42:25,585
LIPIDS.

1113
00:42:25,585 --> 00:42:26,987
WHAT MAKES THEM AND SO AGAIN,

1114
00:42:26,987 --> 00:42:28,388
FOR THIS 1, SINCE WE DIDN'T HAVE

1115
00:42:28,388 --> 00:42:30,457
ANYTHING TO GO WITH, WE WENT AND

1116
00:42:30,457 --> 00:42:31,791
LOOKED IN THE LITERATURE AND

1117
00:42:31,791 --> 00:42:34,661
THERE'S A LOT OF LITERATURE,

1118
00:42:34,661 --> 00:42:37,263
BEAUTIFUL WORK IN THE SEPSIS

1119
00:42:37,263 --> 00:42:40,600
FIELD AND IN COPD AND ASTHMA,

1120
00:42:40,600 --> 00:42:44,871
THAT WAS GENERATED OVER THE

1121
00:42:44,871 --> 00:42:47,707
YEARS THAT SAID THAT ILLUSTRATED

1122
00:42:47,707 --> 00:42:50,243
THAT THESE DAMPS OF EITHER

1123
00:42:50,243 --> 00:42:51,544
MEDIATORS RELEASING IN RESPONSE

1124
00:42:51,544 --> 00:42:54,614
TO DAMAGE, CAN ACTIVATE TLR 4,

1125
00:42:54,614 --> 00:42:57,584
AND THERE WAS A COUPLE OF

1126
00:42:57,584 --> 00:42:59,285
SEMINOLE PAPERS IN THE

1127
00:42:59,285 --> 00:43:00,320
LITERATURE FROM THE COPD FIELD

1128
00:43:00,320 --> 00:43:04,157
AND IN FACT 1 OF MY FIRST

1129
00:43:04,157 --> 00:43:07,127
COLLABORATOR WAS WORKING IN

1130
00:43:07,127 --> 00:43:09,562
COPD, AND THEY WERE FINDING THAT

1131
00:43:09,562 --> 00:43:11,297
ACTIVATION OF TLR4 CAN INCREASE

1132
00:43:11,297 --> 00:43:14,768
S1 P BY ACTIVATING THESE

1133
00:43:14,768 --> 00:43:15,001
ENZYMES.

1134
00:43:15,001 --> 00:43:17,437
SEVERAL MECHANISM IN WHICH THIS

1135
00:43:17,437 --> 00:43:17,871
HAPPENS.

1136
00:43:17,871 --> 00:43:19,806
MORE OVER, SOME ENZYME THAT

1137
00:43:19,806 --> 00:43:24,077
THERE ARE UPSTREAM SUCH AS

1138
00:43:24,077 --> 00:43:25,845
EXAMPLE, CERAMIN ACES OR SINGLE

1139
00:43:25,845 --> 00:43:29,315
PATHWAYS CAN BE ACTIVATED BY

1140
00:43:29,315 --> 00:43:30,250
REACTIVE OXYGEN SPECIES, SO WE

1141
00:43:30,250 --> 00:43:32,152
HAD THIS DATA FROM THE PARALLEL

1142
00:43:32,152 --> 00:43:33,687
FILEDS BUT IN OUR OWN FIELD, WE

1143
00:43:33,687 --> 00:43:41,795
KNOW AND THE TRAUMA OF CHEMO

1144
00:43:41,795 --> 00:43:48,668
THERAPY CAN ALSO INCREASE AND

1145
00:43:48,668 --> 00:43:49,969
THAT SOME MELTALS CAN BIND AND

1146
00:43:49,969 --> 00:43:52,839
TURN ON AND ACTIVATE TLR4 AND WE

1147
00:43:52,839 --> 00:43:55,408
ALSO KNOW THAT CHEMO THERAPY CAN

1148
00:43:55,408 --> 00:43:57,777
ACTIVATE PRODUCTION OF REACTIVE

1149
00:43:57,777 --> 00:44:01,214
OXYGEN SPECIES IN THE CENTRAL

1150
00:44:01,214 --> 00:44:02,582
NERVOUS SYSTEM AND OVER THE

1151
00:44:02,582 --> 00:44:04,017
YEARS I'VE SHOWN YOU NOW THE

1152
00:44:04,017 --> 00:44:06,186
CYTOKINES SO THIS IS JUST A

1153
00:44:06,186 --> 00:44:08,621
HYPOTHESIS AND WE THINK TLR4 IS

1154
00:44:08,621 --> 00:44:12,325
INVOLVED BUT BEFORE WE DIG INTO

1155
00:44:12,325 --> 00:44:15,462
-- MOVE THE HYPOTHESIS OF SIMPLE

1156
00:44:15,462 --> 00:44:17,097
QUESTION WAS THIS ACTIVATION OF

1157
00:44:17,097 --> 00:44:21,101
TLR4 IN THE SPINAL CORD CAUSES

1158
00:44:21,101 --> 00:44:23,670
HYPER SENSITIVITY VIA THE SINGLE

1159
00:44:23,670 --> 00:44:25,739
LIPID METABOLISM AND WE DID A

1160
00:44:25,739 --> 00:44:28,074
SIMPLE EXPERIMENT WHICH IS THE

1161
00:44:28,074 --> 00:44:30,944
CONANICLE ACTIVATOR THE TLR 4,

1162
00:44:30,944 --> 00:44:35,348
IT BINDS CAUSES RECRUITMENT OF

1163
00:44:35,348 --> 00:44:37,217
THE ADAPTOR PROTEINS AND ACT

1164
00:44:37,217 --> 00:44:38,918
VAGALL OF DOWN STREAM SIGNALING

1165
00:44:38,918 --> 00:44:41,321
PATHWAYS AND SO WE GAVE THAT THE

1166
00:44:41,321 --> 00:44:43,056
BEHAVIOR AND YOU CAN SEE HERE

1167
00:44:43,056 --> 00:44:44,591
THAT THE DEMONSTRATION OF

1168
00:44:44,591 --> 00:44:50,964
ENDOTOXIN AS SHOWN BY OTHER

1169
00:44:50,964 --> 00:44:51,765
CAUSES PAIN.

1170
00:44:51,765 --> 00:44:53,500
AND AND ASSOCIATED WITH THE

1171
00:44:53,500 --> 00:44:56,302
DEVELOPMENT OF PAIN WE HAVE THE

1172
00:44:56,302 --> 00:44:57,504
ACTIVATION OF THE ENZYME JUST AS

1173
00:44:57,504 --> 00:45:00,240
PEOPLE FOUND IN OTHER AREAS OF

1174
00:45:00,240 --> 00:45:01,775
ACTIVATION OF TLF 4 CAUSES PAIN

1175
00:45:01,775 --> 00:45:07,313
AND THIS IS MEIATED BY S1 P, BUT

1176
00:45:07,313 --> 00:45:10,517
IS THIS MEDIATED BY THE S1 P

1177
00:45:10,517 --> 00:45:10,784
RECEPTOR.

1178
00:45:10,784 --> 00:45:11,885
AND THE ANSWER TO THAT QUESTION

1179
00:45:11,885 --> 00:45:12,418
IS RIGHT HERE.

1180
00:45:12,418 --> 00:45:15,622
HAD IS THE DEVELOPMENT OF HYPER

1181
00:45:15,622 --> 00:45:16,890
ANNAL GEEZIA, HYPER SENSITIVITY

1182
00:45:16,890 --> 00:45:20,126
TO LPS AND THIS IS COMPLETELY

1183
00:45:20,126 --> 00:45:22,929
BLOCKED WHEN WE GIVE AN

1184
00:45:22,929 --> 00:45:23,396
INHIBITOR OF SPR1.

1185
00:45:23,396 --> 00:45:25,031
THIS IS THE CONTROL TO SHOW THAT

1186
00:45:25,031 --> 00:45:28,902
IN FACT, THE EFFECT OF LPS ARE

1187
00:45:28,902 --> 00:45:31,104
BLOCKED BY TLR4 ANTAGONIST, THIS

1188
00:45:31,104 --> 00:45:33,706
IS WIDELY USED TO BLOCK TLR4

1189
00:45:33,706 --> 00:45:34,440
PATHWAY.

1190
00:45:34,440 --> 00:45:36,442
SO THIS IS OUR HIPOG SIS, AND

1191
00:45:36,442 --> 00:45:37,844
WE'VE ACTUALLY HAD THE GRANT, WE

1192
00:45:37,844 --> 00:45:41,281
HAVE A GRANT NOW, THAT THAT

1193
00:45:41,281 --> 00:45:42,782
INVESTIGATES THE ROLE OF SINGLE

1194
00:45:42,782 --> 00:45:45,351
LIPID IN A NEURAL TOXICITY WHICH

1195
00:45:45,351 --> 00:45:46,619
IS NEURAL COGNITIVE IMPAIRMENT

1196
00:45:46,619 --> 00:45:48,955
AND WE'RE TEASING APART THE ROLE

1197
00:45:48,955 --> 00:45:51,958
OF TLR4 WHICH CELLS THE ASTRO

1198
00:45:51,958 --> 00:45:53,827
SIGHT, MICROGLIA THAT IS

1199
00:45:53,827 --> 00:45:55,295
PRODUCING THE SINGLE LIPIDS AND

1200
00:45:55,295 --> 00:45:58,164
SO FORTH.

1201
00:45:58,164 --> 00:46:00,667
SO, SO THIS IS WHERE WE ARE 14

1202
00:46:00,667 --> 00:46:01,601
YEARS LATER.

1203
00:46:01,601 --> 00:46:04,304
WE FOUND THESE ANTAGONIST HAVE

1204
00:46:04,304 --> 00:46:05,805
NO EFFECT ON PAIN THRESHOLD.

1205
00:46:05,805 --> 00:46:09,075
THEY'RE EFFECTIVE IN MANY MODELS

1206
00:46:09,075 --> 00:46:11,477
NEUROPATHIC PAIN IN MALES AND

1207
00:46:11,477 --> 00:46:13,780
FEMALES, THEY DON'T CAUSE

1208
00:46:13,780 --> 00:46:14,981
ANALGESIC TOLERANCE, THEY DON'T

1209
00:46:14,981 --> 00:46:17,817
CAUSE REWARD BEHAVIORS AND WE

1210
00:46:17,817 --> 00:46:22,989
PUBLISHED AND ARE OPIDDOID

1211
00:46:22,989 --> 00:46:24,824
SPARING, WE IDENTIFIED THAT

1212
00:46:24,824 --> 00:46:30,029
ASTRO SIGHTS ARE IDENTIFIED AS A

1213
00:46:30,029 --> 00:46:31,397
CELLULAR HUB FOR PHARMACOLOGICAL

1214
00:46:31,397 --> 00:46:36,703
ACTION, AND WE ALSO SAID THAT WE

1215
00:46:36,703 --> 00:46:40,974
USED THESE IN NEUROPATHIC PAIN

1216
00:46:40,974 --> 00:46:41,341
STATES.

1217
00:46:41,341 --> 00:46:43,076
SO SO SEVERAL YEARS AGO, THERE

1218
00:46:43,076 --> 00:46:45,411
WAS A MEETING AT NCI AND I

1219
00:46:45,411 --> 00:46:48,982
PRESENTED THE PROJECT IT AND IT

1220
00:46:48,982 --> 00:46:54,921
WAS -- I WAS BLESSED TO

1221
00:46:54,921 --> 00:46:56,656
COLLABORATE WITH CHARLES AT WAKE

1222
00:46:56,656 --> 00:46:57,724
FOREST HE WAS VERY MUCH

1223
00:46:57,724 --> 00:46:59,459
INTERESTED IN THIS PROJECT AND

1224
00:46:59,459 --> 00:47:02,795
WE SAID, LET'S DO APPROVED

1225
00:47:02,795 --> 00:47:04,197
PRINCIPLE TRIAL WHICH WAS VERY

1226
00:47:04,197 --> 00:47:05,365
EXPENSIVE FOR US BAH WE DIDN'T

1227
00:47:05,365 --> 00:47:06,799
GET THE DRUGS FROM THE CUTCHES,

1228
00:47:06,799 --> 00:47:08,534
SO WE HAD TO BUY IT AND THE IDEA

1229
00:47:08,534 --> 00:47:15,975
WAS TO DO IT AS AN ADJUNCT OF P

1230
00:47:15,975 --> 00:47:20,813
A CLITAXEL, TO BLOCK AND

1231
00:47:20,813 --> 00:47:23,082
PROTENTIALLY TREAT CIP IN WOMEN

1232
00:47:23,082 --> 00:47:24,751
FOR BREAST CANCER, HE FOUND A

1233
00:47:24,751 --> 00:47:25,785
COUPLE OF APPROVED TRIAL ANDS

1234
00:47:25,785 --> 00:47:28,254
THEN COVID HIT AND I THINK WE

1235
00:47:28,254 --> 00:47:31,057
RECRUITED LIKE 5 OR 6 PATIENTS

1236
00:47:31,057 --> 00:47:32,225
AND WE HAD TO STOP.

1237
00:47:32,225 --> 00:47:42,702
BUT NOW THAT WE HAVE BETTER

1238
00:47:42,702 --> 00:47:43,736
DRUGS THAN SPHINGO-AND FIND IT

1239
00:47:43,736 --> 00:47:46,072
NOW WITH A CLEANER MORE

1240
00:47:46,072 --> 00:47:48,708
SELECTIVE COMPOUNDS OF ANIMAL.

1241
00:47:48,708 --> 00:47:51,511
SO THIS IS WHERE WE WANT TO GO.

1242
00:47:51,511 --> 00:47:53,846
WHAT IS ALSO BECOMING EXCITING

1243
00:47:53,846 --> 00:47:57,317
IN THIS AREA IS NOW THERE ARE

1244
00:47:57,317 --> 00:47:58,751
MORE THERE ARE PAPERS THAT ARE

1245
00:47:58,751 --> 00:47:59,919
COMING OUT THAT ARE VALIDATING

1246
00:47:59,919 --> 00:48:01,788
WHAT WE AWE IN THE ANIMALS YEARS

1247
00:48:01,788 --> 00:48:03,289
AGO, SO THESE ARE VERY 2 VALID

1248
00:48:03,289 --> 00:48:06,326
AND RELIABLE INTERESTING PAPERS,

1249
00:48:06,326 --> 00:48:08,962
BOTH IN THE CIPN FIELDS WHERE

1250
00:48:08,962 --> 00:48:11,731
THEY ALSO SHOW SIGNIFICANT

1251
00:48:11,731 --> 00:48:17,704
ALTERATIONS SINGLE LIPID

1252
00:48:17,704 --> 00:48:18,471
METABOLISM IN CIPN.

1253
00:48:18,471 --> 00:48:19,906
SO 14 YEARS DOWN THE ROAD,

1254
00:48:19,906 --> 00:48:24,310
HERE'S WHAT WE WANT TO CONSIDER,

1255
00:48:24,310 --> 00:48:27,146
SOME NEUROPATHIC PAIN STATES

1256
00:48:27,146 --> 00:48:30,516
SHOULD BE CONSIDERED AS

1257
00:48:30,516 --> 00:48:33,586
SPHINGOPATHIES WHICH SHOULD BE

1258
00:48:33,586 --> 00:48:37,190
TREATED WITH SINGLE

1259
00:48:37,190 --> 00:48:37,890
SPHINGOLIPID-BASED THERAPIES.

1260
00:48:37,890 --> 00:48:40,393
TO THIS END I STARTED A

1261
00:48:40,393 --> 00:48:42,228
CONSOWRTIUM, STARTED AT THE END

1262
00:48:42,228 --> 00:48:52,005
LAST MONTH CONSISTING OF MYSELF

1263
00:48:52,005 --> 00:48:53,773
AND COLLEAGUES, IT'S A MIXTURE

1264
00:48:53,773 --> 00:48:55,675
OF CLINICAL PEOPLE AS WELL AS

1265
00:48:55,675 --> 00:48:57,844
BASIC SCIENTISTS AND OUR

1266
00:48:57,844 --> 00:48:59,045
THOUGHTS ARE TO REALLY START

1267
00:48:59,045 --> 00:49:01,981
MAKING PEOPLE AWARE OF THIS

1268
00:49:01,981 --> 00:49:04,951
PATHWAYS WHEN PEOPLE THINK

1269
00:49:04,951 --> 00:49:06,786
SPHINGOLIPIDS, THEY THINK LIPIDS

1270
00:49:06,786 --> 00:49:08,121
IN GENERAL, THESE ARE

1271
00:49:08,121 --> 00:49:09,288
SPHINGOLIPIDS AND WE WANT TO

1272
00:49:09,288 --> 00:49:11,290
RAISE AWARE BUSINESS SO WE WILL

1273
00:49:11,290 --> 00:49:13,059
PUBLISH A FIRST DEPOSITION PAPER

1274
00:49:13,059 --> 00:49:13,860
GOING FORWARD.

1275
00:49:13,860 --> 00:49:17,730
WE ALSO THINK THAT SOME OF THE

1276
00:49:17,730 --> 00:49:18,664
SPHINGOLIPIDS BASED ON MARCO'S

1277
00:49:18,664 --> 00:49:22,235
WORK CAN BE USED AS BIOMARKERS

1278
00:49:22,235 --> 00:49:27,140
AND I HAVE A GRANT HERE WITH

1279
00:49:27,140 --> 00:49:31,177
STEPHANIE AT WASH-U, TO LOOK AT

1280
00:49:31,177 --> 00:49:35,148
AND DO SINGEM LIPID ORDER OF

1281
00:49:35,148 --> 00:49:37,116
MICRONSICS AND SMALL FIBER

1282
00:49:37,116 --> 00:49:37,450
NEUROPATHIES.

1283
00:49:37,450 --> 00:49:38,785
SO WHAT IS ALSO BECOMING VERY

1284
00:49:38,785 --> 00:49:41,187
EXCITING IS THAT I'VE TALKED A

1285
00:49:41,187 --> 00:49:43,423
LOT ABOUT THE ROLE OF THE SYSTEM

1286
00:49:43,423 --> 00:49:45,191
RIGHT HERE IN THIS TRAUMATIC

1287
00:49:45,191 --> 00:49:46,692
NERVE INJURY BUT THERE'S A LOT

1288
00:49:46,692 --> 00:49:49,262
OF PAPERS COMING OUT IN A LOT OF

1289
00:49:49,262 --> 00:49:51,664
OTHER INDICATIONS, AND WHEN WE

1290
00:49:51,664 --> 00:49:52,498
STARTED, THERE WAS 0 PAPER ANDS

1291
00:49:52,498 --> 00:49:54,400
NOW YOU CAN SEE THERE ARE MANY

1292
00:49:54,400 --> 00:49:56,702
REHAVE YOUS ARTICLE THAT ARE

1293
00:49:56,702 --> 00:49:57,637
COMING OUT TAKEN--THEY REALLY

1294
00:49:57,637 --> 00:50:01,707
KIND OF HELP VALIDATE AND

1295
00:50:01,707 --> 00:50:02,942
UNDERSCORE HOW PROLIFIC THIS

1296
00:50:02,942 --> 00:50:06,512
FIELD IS, HOPEFULLY GOING TO

1297
00:50:06,512 --> 00:50:06,779
BECOME.

1298
00:50:06,779 --> 00:50:09,682
SO NONE OF THIS WORK WOULD HAVE

1299
00:50:09,682 --> 00:50:12,385
BEEN MADE POSSIBLE WITH A LOT OF

1300
00:50:12,385 --> 00:50:14,487
WORK FROM MY LAB, AND OTHERS

1301
00:50:14,487 --> 00:50:17,623
THAT HAVE DIRECTLY CONTRIBUTED

1302
00:50:17,623 --> 00:50:23,262
TO THIS SPECIFIC PROJECT.

1303
00:50:23,262 --> 00:50:24,530
MY COLLABORATORS, AS WELL AS

1304
00:50:24,530 --> 00:50:25,932
THOSE ASH ROUND THE WORLD THAT

1305
00:50:25,932 --> 00:50:27,200
HAVE JOINED US IN THIS IFORT.

1306
00:50:27,200 --> 00:50:31,737
A LOT OF THE INITIAL PEOPLE

1307
00:50:31,737 --> 00:50:33,239
HERE, YOU SEE, COLLEAGUES HERE

1308
00:50:33,239 --> 00:50:35,208
YOU HAVE NO INVOLVEMENT IN PAIN,

1309
00:50:35,208 --> 00:50:36,542
THEY JUST HELP ME WITH THE

1310
00:50:36,542 --> 00:50:38,811
ANALYSIS OF ALL OF THIS

1311
00:50:38,811 --> 00:50:40,880
INTERESTING ENZYMES THAT MAKE

1312
00:50:40,880 --> 00:50:49,155
SINGLE LIPIDS AND MORE RECENTLY

1313
00:50:49,155 --> 00:50:51,891
WE HAVE ANALYZING AND TREMENDOUS

1314
00:50:51,891 --> 00:50:54,794
SUPPORT FROM OUR COLLEAGUES,

1315
00:50:54,794 --> 00:50:56,562
EVERYBODY AT UNIVERSITY OF

1316
00:50:56,562 --> 00:50:57,797
ARIZONA WERE TRIEWMENTAL IN

1317
00:50:57,797 --> 00:50:59,432
SHOWING THE LACK OF ABUSE

1318
00:50:59,432 --> 00:51:00,867
POTENTIAL IN THE DRUGS IN THE

1319
00:51:00,867 --> 00:51:02,168
ANIMAL MODELS AND OF COURSE NONE

1320
00:51:02,168 --> 00:51:04,604
OF THIS WORK WILL HAPPEN WITHOUT

1321
00:51:04,604 --> 00:51:06,739
YOU KNOW FOUNDATIONS SUCH AS THE

1322
00:51:06,739 --> 00:51:08,274
MAY DAY FUND WHICH WHEN I

1323
00:51:08,274 --> 00:51:09,709
STARTED I COULDN'T PUT AN RO-1

1324
00:51:09,709 --> 00:51:11,010
TOGETHER BECAUSE IT WAS A NEW

1325
00:51:11,010 --> 00:51:13,379
FIELD AND IT WASN'T -- IT WAS

1326
00:51:13,379 --> 00:51:14,547
STILL VERY NEW EMPLOY THEY

1327
00:51:14,547 --> 00:51:16,282
JUCHED ON BOARD AND PROVIDED US

1328
00:51:16,282 --> 00:51:19,852
WITH FUNDING THAT,A LOWED US TO

1329
00:51:19,852 --> 00:51:23,956
PROVIDE THE IPT GREATER  DATA SO

1330
00:51:23,956 --> 00:51:26,459
FOUNDATION VS BEEN WONDERFUL

1331
00:51:26,459 --> 00:51:30,963
INSTITUTIONS TO PROVOID HELP TO

1332
00:51:30,963 --> 00:51:32,565
INVESTIGATORS AND THE NATIONAL

1333
00:51:32,565 --> 00:51:35,134
IBSITUTES OF HEALTH WE HAD

1334
00:51:35,134 --> 00:51:37,136
FUNDING FROM NINDS, NCI AND

1335
00:51:37,136 --> 00:51:38,504
NIDA, THAT WITHOUT THEIR

1336
00:51:38,504 --> 00:51:42,241
SUPPORT, WE REALLY CANNOT

1337
00:51:42,241 --> 00:51:43,176
ADVANCE KNOWLEDGE AND REALLY

1338
00:51:43,176 --> 00:51:45,511
MAKE AN IMPACT IN HUMANS LIFE,

1339
00:51:45,511 --> 00:51:48,314
SO I'M REALLY, REALLY GRATEFUL

1340
00:51:48,314 --> 00:51:50,850
FOR THEIR SUPPORT AND I'M

1341
00:51:50,850 --> 00:51:53,019
GRATEFUL FOR THE INVITATION,

1342
00:51:53,019 --> 00:51:54,420
IT'S REALLY AN HONOR AND I'M

1343
00:51:54,420 --> 00:52:00,393
OPEN TO ANY QUESTION, THANK YOU.

1344
00:52:00,393 --> 00:52:00,693
[ APPLAUSE ]

1345
00:52:00,693 --> 00:52:01,994
>> HAPPY TO TAKE QUESTIONS
FROM

1346
00:52:01,994 --> 00:52:03,095
THE ROOM, WE HAVE SEVERAL ONLINE

1347
00:52:03,095 --> 00:52:04,931
IF YOU WOULD LIKE TO GET STARTED

1348
00:52:04,931 --> 00:52:08,234
WITH 1, MAYBE START WITH 1.

1349
00:52:08,234 --> 00:52:09,035
OKAY.

1350
00:52:09,035 --> 00:52:11,971
THE S1 PR1 ANTAGONIST REDUCE

1351
00:52:11,971 --> 00:52:13,873
PAIN RESPONSE BUT DO THEY

1352
00:52:13,873 --> 00:52:20,012
REVERSE INFLAMMATION RESPONSES,

1353
00:52:20,012 --> 00:52:21,881
THE RECEPTORS ON THE SURFACE,

1354
00:52:21,881 --> 00:52:23,950
DPLEEL CELLS, DO THEY GET

1355
00:52:23,950 --> 00:52:25,284
INTERNALIZED AND THE ASTRO SIGHT

1356
00:52:25,284 --> 00:52:26,886
DESTROYED SO THERE IS NO IMMUNE

1357
00:52:26,886 --> 00:52:30,223
RESPONSE THAT WILL REMOVE THE

1358
00:52:30,223 --> 00:52:32,258
INFLAMMATORY RESPONSE AND

1359
00:52:32,258 --> 00:52:33,159
THEREBY CURE DISEASE?

1360
00:52:33,159 --> 00:52:36,495
NTHAT'S A GOOD QUESTION.

1361
00:52:36,495 --> 00:52:42,535
SO WE HAVE LOOKED AT -- IN THE

1362
00:52:42,535 --> 00:52:43,669
CANCER INDUCED NEUROPATHIC PAIN

1363
00:52:43,669 --> 00:52:44,770
STATES ALL OF THOSE EXPERIMENTS

1364
00:52:44,770 --> 00:52:47,039
WERE DONE IN A PROPHYLACTIC

1365
00:52:47,039 --> 00:52:48,674
MODALITY AND WE FOUND THAT YES,

1366
00:52:48,674 --> 00:52:53,212
WHEN WE BLOCK THE RECEPTOR, WE

1367
00:52:53,212 --> 00:52:55,414
CAN ATTENUATE THE INFLAMMATORY

1368
00:52:55,414 --> 00:52:57,383
RESPONSE, IN THE MODEL OF

1369
00:52:57,383 --> 00:52:58,417
TRAUMATIC NERVE INJURY, THAT

1370
00:52:58,417 --> 00:53:04,223
EXPERIMENTS THAT I SHOWED YOU

1371
00:53:04,223 --> 00:53:06,792
WITH IL1 BETA, WE FOUND THAT IN

1372
00:53:06,792 --> 00:53:08,060
A THERAPEUTIC MODALITY WE COULD

1373
00:53:08,060 --> 00:53:10,396
ALSO INHIBIT THE DEVELOPMENT OF

1374
00:53:10,396 --> 00:53:13,566
THE INCREASED PRODUCTION OF IL1

1375
00:53:13,566 --> 00:53:14,333
BETA.

1376
00:53:14,333 --> 00:53:16,168
SO THOSE EXPERIMENTS WERE DONE

1377
00:53:16,168 --> 00:53:19,905
WITH BOTH FUNCTIONAL ANTAGONISTS

1378
00:53:19,905 --> 00:53:21,274
WHICH WOULD CAUSE PERMANENT

1379
00:53:21,274 --> 00:53:23,142
DEGRADATION OF THAT RECEPTOR

1380
00:53:23,142 --> 00:53:24,977
RESUMABLY IN A CELL AND ASTRO

1381
00:53:24,977 --> 00:53:26,512
SIGHT AND ANOTHER CELL TYPE BUT

1382
00:53:26,512 --> 00:53:29,315
ALSO WITH THE COMPETITIVE SPR1

1383
00:53:29,315 --> 00:53:30,850
ANTAGONIST WHICH ARE INHIBITING

1384
00:53:30,850 --> 00:53:31,917
THE RECEPTOR, I DON'T KNOW IF

1385
00:53:31,917 --> 00:53:34,654
THAT ANSWERS THE QUESTION.

1386
00:53:34,654 --> 00:53:39,025
>> IT WASN'T MY QUESTION.

1387
00:53:39,025 --> 00:53:40,760
[LAUGHTER]

1388
00:53:40,760 --> 00:53:43,162
>> HEY, SO YOU'RE PROBABLY
SEE

1389
00:53:43,162 --> 00:53:44,330
MULTIPLE POTENTIAL TARGETS EVERY

1390
00:53:44,330 --> 00:53:47,199
DAY THROUGH LIKE LITERATURE

1391
00:53:47,199 --> 00:53:49,168
REVIEWS AND RNASEQ ANALYSIS SO

1392
00:53:49,168 --> 00:53:50,836
YOU DO YOU EVALUATE A TARGET

1393
00:53:50,836 --> 00:53:53,005
POTENTIAL FOR PAIN RELIEF BEFORE

1394
00:53:53,005 --> 00:53:59,312
DECIDING TO CONDUCT AN

1395
00:53:59,312 --> 00:53:59,612
EXPERIMENT?

1396
00:53:59,612 --> 00:54:01,914
, OKAY, SAY THAT AGAIN.

1397
00:54:01,914 --> 00:54:03,616
>> YEAH, SO LIKE YOU
PROBABLY

1398
00:54:03,616 --> 00:54:06,085
SEE A BUNCH OF TARGETS THROUGH

1399
00:54:06,085 --> 00:54:08,587
LITERATURE REVIEWS LIKE

1400
00:54:08,587 --> 00:54:09,922
POTENTIAL GPC Rs OR GENES THAT

1401
00:54:09,922 --> 00:54:14,026
ARE HIGHLY EXPRESSED IN CERTAIN

1402
00:54:14,026 --> 00:54:17,129
AREAS OR RNASEQ ANALYSIS WHERE

1403
00:54:17,129 --> 00:54:19,098
DIFFERENT GENES ARE UPREGULATED

1404
00:54:19,098 --> 00:54:20,299
HOW DO YOU PERSONALLY EVALUATE

1405
00:54:20,299 --> 00:54:21,667
TO EMBARK ON AN INVESTIGATION

1406
00:54:21,667 --> 00:54:24,170
BEFORE YOU START --

1407
00:54:24,170 --> 00:54:25,438
>> AH, YES, I UNDERSTAND.

1408
00:54:25,438 --> 00:54:26,605
I UNDERSTAND.

1409
00:54:26,605 --> 00:54:32,378
OKAY, SO, ON THIS PARTICULAR 1,

1410
00:54:32,378 --> 00:54:36,582
THE DATA WAS VERY, VERY

1411
00:54:36,582 --> 00:54:40,186
COMPELLING AND THE FACT THAT

1412
00:54:40,186 --> 00:54:42,488
THERE WERE DRUGS THAT WERE

1413
00:54:42,488 --> 00:54:44,423
APPROVED FOR INDICATION RAISED

1414
00:54:44,423 --> 00:54:46,926
MY EXCITEMENT SO THAT IS 1 THE

1415
00:54:46,926 --> 00:54:48,627
REASONS WHY I DECIDE TO HONE IN

1416
00:54:48,627 --> 00:54:50,429
ON THIS TARGET.

1417
00:54:50,429 --> 00:54:52,665
ANOTHER TARGET, 1 I'VE BEEN

1418
00:54:52,665 --> 00:54:56,135
WORKING ON WITH DR. JACOBSEN FOR

1419
00:54:56,135 --> 00:54:57,670
MANY YEARS WAS THE SAME REASON.

1420
00:54:57,670 --> 00:54:59,605
WE HAD THE TARGET IDENTIFIED IN

1421
00:54:59,605 --> 00:55:02,108
THE ANIMAL MODELS ISSUE THE

1422
00:55:02,108 --> 00:55:04,243
RECEPTOR PRESENT IN HUMAN

1423
00:55:04,243 --> 00:55:06,011
TISSUES AND IN RODENTS OF THE

1424
00:55:06,011 --> 00:55:07,947
RIGHT SITES AND THERE WERE DRUGS

1425
00:55:07,947 --> 00:55:10,282
THAT WERE MOVING FORWARD AS AN

1426
00:55:10,282 --> 00:55:12,551
ANTICANCER THERAPY FOR EXAMPLE,

1427
00:55:12,551 --> 00:55:15,421
THAT RAISES EXCITEMENT TO ME SO

1428
00:55:15,421 --> 00:55:20,493
WHEN I HAVE THAT COMBINATION,

1429
00:55:20,493 --> 00:55:23,696
OTHER TARGETS THAT WERE BASED ON

1430
00:55:23,696 --> 00:55:26,932
RECEPTOR PRESENCE IN THE HUMAN

1431
00:55:26,932 --> 00:55:30,236
TISSUE, HOW ROBUST THE

1432
00:55:30,236 --> 00:55:33,072
PHARMACOLOGY IS, VISIBILITY OF

1433
00:55:33,072 --> 00:55:40,980
MAKING LIGANDS AND SO FORTH.

1434
00:55:40,980 --> 00:55:42,481
SO WE TEASE THE PATHWAY AT

1435
00:55:42,481 --> 00:55:45,217
MAXIMUM AND IF THE DATA KEEPS

1436
00:55:45,217 --> 00:55:47,186
COMING BACK AS BEING VERY

1437
00:55:47,186 --> 00:55:48,587
EXCITING WE PURSUE IT, IF THE

1438
00:55:48,587 --> 00:55:51,557
DATA IS NOT EXCITING AFTER A

1439
00:55:51,557 --> 00:55:52,992
GOOD TRY, WE PUT IT ON THE SIDE.

1440
00:55:52,992 --> 00:55:56,729
AND WE PUT ON THE SIDE SEVERAL

1441
00:55:56,729 --> 00:55:56,962
PROGECS.

1442
00:55:56,962 --> 00:55:57,363
-- PROJECTS.

1443
00:55:57,363 --> 00:55:59,665
DOES THAT ANSWER THE QUESTION?

1444
00:55:59,665 --> 00:56:03,836
>> YES, IT DOES, THANK
YOU.

1445
00:56:03,836 --> 00:56:04,637
>> TOUGH QUESTION COMES
NOW.

1446
00:56:04,637 --> 00:56:07,807
>> NO, NO, THAT WAS A
BEAUTIFUL

1447
00:56:07,807 --> 00:56:08,541
TALK.

1448
00:56:08,541 --> 00:56:12,578
I HAVE 2 UNRELATED QUESTIONS, 1

1449
00:56:12,578 --> 00:56:16,515
OF THEM, IS YOU MENTIONED THAT

1450
00:56:16,515 --> 00:56:19,385
THE EFFECTS OF THE DRUG THAT

1451
00:56:19,385 --> 00:56:21,153
THEY'RE GOOD IN BOTH MALE ANDS

1452
00:56:21,153 --> 00:56:22,354
FEMALES WHICH IS FANTASTIC BUT

1453
00:56:22,354 --> 00:56:26,091
IT WAS -- I WAS CURIOUS TO SEE,

1454
00:56:26,091 --> 00:56:29,295
THAT THE -- OR SURPRISED TO SEE

1455
00:56:29,295 --> 00:56:31,964
THAT THE MECHANISTIC PART

1456
00:56:31,964 --> 00:56:33,632
INVOLVED ASTRO GLUE MARIOUSA AND

1457
00:56:33,632 --> 00:56:35,568
TELOMERE SHORTENING LIKE

1458
00:56:35,568 --> 00:56:38,804
RECEPTORS WHICH ARE -- MICROGLIA

1459
00:56:38,804 --> 00:56:39,872
AND TOLL-LIKE RECEPTORS WHICH

1460
00:56:39,872 --> 00:56:41,373
ARE SEX DEPENDENT SO I WANTED TO

1461
00:56:41,373 --> 00:56:43,576
KNOW IF THE MECHANISTIC PART WAS

1462
00:56:43,576 --> 00:56:44,910
ALSO DONE IN BOTH SEXES AND IF

1463
00:56:44,910 --> 00:56:46,245
IT,A PLAYS TO THEM IN SAME WAY

1464
00:56:46,245 --> 00:56:48,380
AND YOUR THOUS ABOUT HOW IT GOES

1465
00:56:48,380 --> 00:56:50,349
WITH THE PRIOR LITERATURE

1466
00:56:50,349 --> 00:56:53,519
SHOWING SEX DIFFERENCES IN THESE

1467
00:56:53,519 --> 00:56:56,388
2 ASTRO SIGHTS AND TOLL-LIKE

1468
00:56:56,388 --> 00:56:56,655
RECEPTORS?

1469
00:56:56,655 --> 00:56:57,957
AND THEN THE OTHER 1 IS

1470
00:56:57,957 --> 00:57:00,392
UNRELATED SO I CAN GO AFTER HIM

1471
00:57:00,392 --> 00:57:02,528
NOKAY, SO, THAT'S A VERY GOOD

1472
00:57:02,528 --> 00:57:03,095
QUESTION.

1473
00:57:03,095 --> 00:57:04,663
ALL OF THE -- EARLY EARLY DATA

1474
00:57:04,663 --> 00:57:07,299
ISSUES THE 1 WHERE WE START

1475
00:57:07,299 --> 00:57:10,836
INDEED 2009, THAT WAS ALL DONE

1476
00:57:10,836 --> 00:57:12,738
IN MALES, SO ALL THE

1477
00:57:12,738 --> 00:57:14,440
BIOCHEMISTRY WAS DONE IN MALES

1478
00:57:14,440 --> 00:57:16,208
BUT THEN WE EVALUATED THE

1479
00:57:16,208 --> 00:57:19,411
RESPONSE OF MALES AND FEMALES TO

1480
00:57:19,411 --> 00:57:21,213
THE DRUG AND WE FOUND NO

1481
00:57:21,213 --> 00:57:22,281
DIFFERENCE WHATSOEVER IN THE

1482
00:57:22,281 --> 00:57:27,987
MALES AND THE FEMALES IN TERMS

1483
00:57:27,987 --> 00:57:31,290
OF DRUG RESPONSE. 

1484
00:57:31,290 --> 00:57:33,392
WITH THAT SAID --

1485
00:57:33,392 --> 00:57:33,959
>> THE MECHANISMS --

1486
00:57:33,959 --> 00:57:36,128
>> SO SINCE WE DIDN'T FIND
ANY

1487
00:57:36,128 --> 00:57:37,696
DIFFERENCE IN DRUG RESPONSE, WE

1488
00:57:37,696 --> 00:57:39,698
DIDN'T GO AND LOOK AT MECHANISM

1489
00:57:39,698 --> 00:57:42,535
BECAUSE WE MAINLY INTERESTED IN

1490
00:57:42,535 --> 00:57:43,702
DOES THE DRUG WORK IN THE

1491
00:57:43,702 --> 00:57:45,337
FEMALES AND DOES IT WORK IN THE

1492
00:57:45,337 --> 00:57:47,306
MALES, AND IF THE ANSWER TO THAT

1493
00:57:47,306 --> 00:57:49,642
WAS YES TWORKS EQUALLY EFFECTIVE

1494
00:57:49,642 --> 00:57:51,176
WITH EVERY SINGLE DRUG IN BOTH

1495
00:57:51,176 --> 00:57:52,778
MALES AND FEMALES THEN WE DIDN'T

1496
00:57:52,778 --> 00:57:54,647
GO AND PURSUE ANY BIOCHEMISTRY

1497
00:57:54,647 --> 00:57:56,382
SO I CAN'T ANSWER YOU THAT.

1498
00:57:56,382 --> 00:57:57,349
THERE'S OHM 1 EXAMPLE THAT WE

1499
00:57:57,349 --> 00:58:00,986
SAW A DIFFERENCE AND THAT WAS

1500
00:58:00,986 --> 00:58:02,922
WITH BOTIZAMIB, AND THAT INDUCED

1501
00:58:02,922 --> 00:58:10,095
PAIN IS IN FEMALE IS NOT

1502
00:58:10,095 --> 00:58:11,363
AFFECTED BY INTERFERING WITH

1503
00:58:11,363 --> 00:58:12,998
THIS PATHWAY AND WE PUBLISHED

1504
00:58:12,998 --> 00:58:13,232
THAT.

1505
00:58:13,232 --> 00:58:15,935
AND IN THAT CASE, WE DID DO THE

1506
00:58:15,935 --> 00:58:17,903
BIOCHEMISTRY BUT WE DIDN'T DO

1507
00:58:17,903 --> 00:58:18,837
SIGNAL PATHWAYS, WHATEVER, WE

1508
00:58:18,837 --> 00:58:20,105
WENT VERY SIMPLE BECAUSE I

1509
00:58:20,105 --> 00:58:21,774
DIDN'T WANT TO GET BOGGED DOWN

1510
00:58:21,774 --> 00:58:23,008
WITH -- SO WE JUST LOOKED AND

1511
00:58:23,008 --> 00:58:24,710
IT,A PEERED TO BE A DIFFERENCE

1512
00:58:24,710 --> 00:58:27,046
IN EXPRESSION LEVELS OF THE

1513
00:58:27,046 --> 00:58:30,082
RECEPTORS IN THE SPINAL CORD

1514
00:58:30,082 --> 00:58:31,483
MALE VERSUS FEMALE SO WE THINK

1515
00:58:31,483 --> 00:58:33,052
THAT MAY BE 1 EXPLANATION BUT WE

1516
00:58:33,052 --> 00:58:34,653
JUST PUBLISHED A PAPER BUT THAT

1517
00:58:34,653 --> 00:58:35,387
INFORMATION WAS VERY IMPORTANT

1518
00:58:35,387 --> 00:58:38,324
BECAUSE IT MEANS THAT WHEN WE GO

1519
00:58:38,324 --> 00:58:42,461
AND DO, AN UMBRELLA CLINICAL

1520
00:58:42,461 --> 00:58:45,898
TRIALS, CASE, WE WOULD NOT USE

1521
00:58:45,898 --> 00:58:46,565
PROTEIN COMPLEXIOSOME INHIBITORS

1522
00:58:46,565 --> 00:58:48,400
FOR THE BLOOD CANC EWE WOULD

1523
00:58:48,400 --> 00:58:49,168
JUST FOCUS ON WHAT WE HAVE THE

1524
00:58:49,168 --> 00:58:50,970
DAILY BASIS THEA WITH THE

1525
00:58:50,970 --> 00:58:53,305
PLATINUM BASED DRUGS AND THE

1526
00:58:53,305 --> 00:58:55,407
TAXINS.

1527
00:58:55,407 --> 00:58:57,109
>> GREAT.

1528
00:58:57,109 --> 00:58:59,011
THANK YOU.

1529
00:58:59,011 --> 00:58:59,445
>> OKAY.

1530
00:58:59,445 --> 00:59:00,746
>> THANK YOU FOR AN
EXACTLIENT

1531
00:59:00,746 --> 00:59:00,980
TALK.

1532
00:59:00,980 --> 00:59:08,687
WE HAVE BEEN USING FTY720 IN OUR

1533
00:59:08,687 --> 00:59:10,356
LAB TO PREVENT T-CELLS FROM

1534
00:59:10,356 --> 00:59:12,424
LEAVING THE LYMPHNODES IS THAT

1535
00:59:12,424 --> 00:59:14,126
POSSIBLY PLAYING A PART IN THE

1536
00:59:14,126 --> 00:59:16,328
MECHANISMS YOU ARE PROPOSING

1537
00:59:16,328 --> 00:59:16,528
HERE?

1538
00:59:16,528 --> 00:59:18,731
>> I'M GLAD YOU ASKED
THIS,

1539
00:59:18,731 --> 00:59:20,666
BECAUSE I FORGOT TO SAY THAT THE

1540
00:59:20,666 --> 00:59:23,535
DOSES WE USE FOR THESE DRUGS ARE

1541
00:59:23,535 --> 00:59:25,504
10-30 FOLD LOWER THAN THOSE THAT

1542
00:59:25,504 --> 00:59:27,272
ARE NEEDED TO BLOCK LYMPHOCYTE

1543
00:59:27,272 --> 00:59:32,711
EGRESS FROM THE LYMPHNODES.

1544
00:59:32,711 --> 00:59:37,783
SO, I DON'T THINK, ACTUALLY WE

1545
00:59:37,783 --> 00:59:39,718
PUBLISHED THAT AN IMPORTANT

1546
00:59:39,718 --> 00:59:43,355
MECHANISM WHEREBY THESE DRUGS

1547
00:59:43,355 --> 00:59:44,823
INHIBIT NEUROPATHIC PAIN STATES

1548
00:59:44,823 --> 00:59:47,393
BY BLOCKING THE PROGRESSION OF

1549
00:59:47,393 --> 00:59:47,693
LYMPHOCYTES.

1550
00:59:47,693 --> 00:59:48,260
>> THANK YOU.

1551
00:59:48,260 --> 00:59:49,662
>> I THINK IT'S MAYBE IN
THE

1552
00:59:49,662 --> 00:59:50,729
CENTRAL NERVOUS SYSTEM AND THE

1553
00:59:50,729 --> 00:59:54,166
DRUG THAT I'VE SEWN BEFORE THE

1554
00:59:54,166 --> 00:59:57,836
S1 PR1 AGONIST, COMPLETELY

1555
00:59:57,836 --> 00:59:59,538
PREVENTS LYMPHOCYTE EGRESS,

1556
00:59:59,538 --> 01:00:02,508
FACAS FACT, WE HAVE TESTED THE

1557
01:00:02,508 --> 01:00:04,977
DRUG AT 20 MPK, PEOPLE THOUGHT I

1558
01:00:04,977 --> 01:00:06,645
WAS CRAZY TO GO AS HIGH AS THAT

1559
01:00:06,645 --> 01:00:13,352
BUT I WANTED TO PROVE MY POINT

1560
01:00:13,352 --> 01:00:14,620
THAT AGGRESSION WAS COMPLETELY

1561
01:00:14,620 --> 01:00:15,654
BLOCKED AND NO EFFECT ON THE

1562
01:00:15,654 --> 01:00:16,555
PAIN RESPONSE.

1563
01:00:16,555 --> 01:00:17,423
>> THANK YOU.

1564
01:00:17,423 --> 01:00:18,757
>> YEAH.

1565
01:00:18,757 --> 01:00:20,993
>> OVER HERE AND HERE.

1566
01:00:20,993 --> 01:00:22,094
NVERY INTERESTING TALK.

1567
01:00:22,094 --> 01:00:23,595
DO YOU THINK THESE COMPOUNDS

1568
01:00:23,595 --> 01:00:25,664
THAT YOU'RE MAINLY USING IN

1569
01:00:25,664 --> 01:00:28,067
CHEEM OR THE--BUT ACTIVITIES AND

1570
01:00:28,067 --> 01:00:29,468
PROJECTSY INDUCED PERIPHERAL

1571
01:00:29,468 --> 01:00:30,302
NEUROPEN MEETINGALATHY WOULD

1572
01:00:30,302 --> 01:00:33,272
ALSO BE ACTIVE IN PEOPLE WITH

1573
01:00:33,272 --> 01:00:34,840
NERVE INJURY INDUCED

1574
01:00:34,840 --> 01:00:38,410
NEUROPATHIES SUCH AS AMPUTATION

1575
01:00:38,410 --> 01:00:38,977
NEUROMA, PAINFULLASMUTATION

1576
01:00:38,977 --> 01:00:41,180
NEUROMA MAY HAVE A PERIPHERAL

1577
01:00:41,180 --> 01:00:46,652
GENERATOR THAN A CNS SITE OF

1578
01:00:46,652 --> 01:00:47,786
ACTION, MAYBE A NONASTRO SIGHT

1579
01:00:47,786 --> 01:00:50,189
KIND OF THING.

1580
01:00:50,189 --> 01:00:52,725
>> I THINK THE EFFICACY
WILL BE

1581
01:00:52,725 --> 01:00:55,894
LESS THAN THE 1S THAT I JUST

1582
01:00:55,894 --> 01:00:58,731
DESCRIBED, LIKE THE TRAUMATIC

1583
01:00:58,731 --> 01:00:59,798
NERVE INJURIES OR CHEMO THERAPY

1584
01:00:59,798 --> 01:01:01,533
EMPLOY SO WITH WE LOOK FOR

1585
01:01:01,533 --> 01:01:06,572
EXAMPLE, WHEN WE TART WITH

1586
01:01:06,572 --> 01:01:09,942
CARAGENEIN POST OP PAIN, YOU

1587
01:01:09,942 --> 01:01:12,211
NEED LARGE DOSES TO SEE AN

1588
01:01:12,211 --> 01:01:14,379
EFFECT EMPLOY SO SOME OF THESE

1589
01:01:14,379 --> 01:01:19,251
DOSES ARE, YOU KNOW 0-POINTS, 1

1590
01:01:19,251 --> 01:01:21,520
MPK, IN THESE MODELS YOU WE HAVE

1591
01:01:21,520 --> 01:01:26,558
TO GIVE 30 M PK,.

1592
01:01:26,558 --> 01:01:27,226
>> INTERESTING.

1593
01:01:27,226 --> 01:01:29,695
>> YEAH, THANK YOU
>>  THANK

1594
01:01:29,695 --> 01:01:30,229
YOU.

1595
01:01:30,229 --> 01:01:34,500
>> YEAH, SO MY SECOND
QUESTION

1596
01:01:34,500 --> 01:01:36,135
WAS RELATED KIND OF TO THE

1597
01:01:36,135 --> 01:01:37,636
DRAWING YOU HAVE THERE AND ALSO

1598
01:01:37,636 --> 01:01:39,538
PART OF YOUR --

1599
01:01:39,538 --> 01:01:41,140
>> WHICH 1?

1600
01:01:41,140 --> 01:01:42,708
>> THAT PAINTING.

1601
01:01:42,708 --> 01:01:44,743
OF THE EFFECTIVE PART OF PAIN.

1602
01:01:44,743 --> 01:01:47,846
SO WE KNOW THAT 1 OF THE BIG

1603
01:01:47,846 --> 01:01:50,716
EFFECTS OF PAIN IS THE AFFECTED

1604
01:01:50,716 --> 01:01:53,352
CO-MORBIDITIES AND YOU INCLUDED

1605
01:01:53,352 --> 01:01:55,354
THAT IN YOUR INTRODUCTION SO I

1606
01:01:55,354 --> 01:01:56,588
WAS WONDERING, YOU MENTIONED

1607
01:01:56,588 --> 01:01:59,758
THAT YOU'VE DONE THE CPA, AND

1608
01:01:59,758 --> 01:02:02,594
CPP, I THINK.

1609
01:02:02,594 --> 01:02:03,762
>> CPP, NYEAH, CPPBUT I
WAS

1610
01:02:03,762 --> 01:02:07,432
WONDERING IF YOU HAVE BECAUSE OF

1611
01:02:07,432 --> 01:02:08,734
THE TREMENDOUS POTENTIAL

1612
01:02:08,734 --> 01:02:09,401
THERAPEUTIC VALUE OF THESE

1613
01:02:09,401 --> 01:02:12,771
STROKES, HAVE YOU LOOKED AT THE

1614
01:02:12,771 --> 01:02:14,773
EFFECTS ON POTENTIAL LIKE

1615
01:02:14,773 --> 01:02:16,608
EFFECTIVE CO-MORBIDITIES OR YOU

1616
01:02:16,608 --> 01:02:18,177
KNOW BRAIN MECHANISMS OR THINGS

1617
01:02:18,177 --> 01:02:18,944
LOAMACYIC THAT.

1618
01:02:18,944 --> 01:02:21,547
>> NO, WE HAVEN'T -- WE
HAVE NOT

1619
01:02:21,547 --> 01:02:22,815
DONE ANY OF THAT.

1620
01:02:22,815 --> 01:02:24,216
THE LAST EXPERIMENT THAT WE DID

1621
01:02:24,216 --> 01:02:25,184
BECAUSE WE'RE MOVING A LITTLE

1622
01:02:25,184 --> 01:02:28,420
BIT AWAY FROM SPINAL CORD IS

1623
01:02:28,420 --> 01:02:30,389
LOOKING AT THE RVM.

1624
01:02:30,389 --> 01:02:32,524
SO THAT PAPER, WE'VE ACTUALLY

1625
01:02:32,524 --> 01:02:33,192
DONE TRANSCRIPTOMICS SO THE

1626
01:02:33,192 --> 01:02:35,360
BOTTOM LINE IS THAT IF WE GIVE

1627
01:02:35,360 --> 01:02:37,729
THE COMPOUND IN THE RBM, WE CAN

1628
01:02:37,729 --> 01:02:41,366
ALSO REVERSE 92URE O PATHIC PAIN

1629
01:02:41,366 --> 01:02:43,669
AND SINGLE CELL RNASEQ IN THE

1630
01:02:43,669 --> 01:02:44,870
RBM AND IDENTIFIED SOME

1631
01:02:44,870 --> 01:02:45,637
INTERESTING PATHWAYS, ABOUT YOU

1632
01:02:45,637 --> 01:02:47,606
WE HAVE NOT DONE THOSE

1633
01:02:47,606 --> 01:02:48,073
EXPERIMENTS.

1634
01:02:48,073 --> 01:02:50,375
I THINK HERE, WE'VE GOT 14 YEARS

1635
01:02:50,375 --> 01:02:55,647
WORTH OF DATA, THAT BEING, YOU

1636
01:02:55,647 --> 01:02:57,115
KNOW PRODUCED REPRODUCED AND

1637
01:02:57,115 --> 01:03:00,752
ADVANCED BY MANY GROUPS, NOW YOU

1638
01:03:00,752 --> 01:03:03,021
HAVE CLINICAL EVIDENCE COMING

1639
01:03:03,021 --> 01:03:05,724
OUT THAT IT'S TIME TO REALLY

1640
01:03:05,724 --> 01:03:07,626
KIND OF THINK ABOUT REPURPOSING

1641
01:03:07,626 --> 01:03:08,927
AND FORGET ABOUT THE ANIMAL

1642
01:03:08,927 --> 01:03:10,963
WORK, THE DRUGS HAVE BEEN

1643
01:03:10,963 --> 01:03:13,599
APPROVED SINCE 2010 FOR MULTIPLE

1644
01:03:13,599 --> 01:03:14,633
SCLEROSIS, THESE PATE VS A

1645
01:03:14,633 --> 01:03:21,874
LITTLE BIT OF A FIRST ON DOSE, A

1646
01:03:21,874 --> 01:03:23,809
LITTLE CARDIA, IN .5% OF THE

1647
01:03:23,809 --> 01:03:24,543
PATIENTS, IT'S THE FIRST DOSE

1648
01:03:24,543 --> 01:03:25,711
BECAUSE THEY HAVE TO BE IN THE

1649
01:03:25,711 --> 01:03:27,813
CLINIC BUT THEN AFTER THE SECOND

1650
01:03:27,813 --> 01:03:30,515
DOSE, THERE'S NO BRADYCARDIA

1651
01:03:30,515 --> 01:03:30,816
WHATSOEVER.

1652
01:03:30,816 --> 01:03:32,885
THE NEWER DRUG HAVE AN IMPROVED

1653
01:03:32,885 --> 01:03:34,620
PROFILE BUT WE HAVE NOW 15 YEARS

1654
01:03:34,620 --> 01:03:37,489
WORTH OF DATA FROM HUMANS AND

1655
01:03:37,489 --> 01:03:40,659
WHERE WE'RE STUCK IS THE ABILITY

1656
01:03:40,659 --> 01:03:41,493
TO DO THIS CLINICAL TRIALS

1657
01:03:41,493 --> 01:03:44,563
BECAUSE WE DON'T HAVE THE DRUG

1658
01:03:44,563 --> 01:03:46,865
TO DO THE TRIAL AND THE MONEY.

1659
01:03:46,865 --> 01:03:48,533
SO, I THINK I'M GOING TO GO

1660
01:03:48,533 --> 01:03:49,935
START BANGING ON THE DOOR AGAIN

1661
01:03:49,935 --> 01:03:53,772
ON COMPANIES TO SEE IF THEY CAN

1662
01:03:53,772 --> 01:03:54,973
PROVIDE MONEY OR IF SOMEBODY

1663
01:03:54,973 --> 01:03:56,775
WANTS TO DO PROOF OF PRINCIPLE.

1664
01:03:56,775 --> 01:03:59,077
BUT AS I MENTIONED THEY'RE

1665
01:03:59,077 --> 01:04:05,284
MOVING FORWARD FOR ULCRATIVE

1666
01:04:05,284 --> 01:04:13,859
COLITIS AND SORTING  -- PSORAIS,

1667
01:04:13,859 --> 01:04:17,796
NO MORE ANIMAL WORK, GO WITH

1668
01:04:17,796 --> 01:04:18,130
HUMANS.

1669
01:04:18,130 --> 01:04:18,563
>> LAST QUESTION.

1670
01:04:18,563 --> 01:04:19,865
>> THANK YOU FOR THE
WONDERFUL

1671
01:04:19,865 --> 01:04:22,701
TALK, I WAS WONDERING ABOUT

1672
01:04:22,701 --> 01:04:26,371
CENTRAL VERSE US   PERRIFFERAL

1673
01:04:26,371 --> 01:04:28,073
CENTER FOR EXCELLENCE ON AGINGS,

1674
01:04:28,073 --> 01:04:29,875
I WAS WONDERING IF MOVING

1675
01:04:29,875 --> 01:04:33,211
FORWARD YOU COULD GIVE THEM

1676
01:04:33,211 --> 01:04:35,013
PERIPHERALLY INSTEAD OF INTRA

1677
01:04:35,013 --> 01:04:36,982
FECALLY, SO I WAS WONDERING HOW

1678
01:04:36,982 --> 01:04:39,584
THEY CROSS BLOOD BRAIN BARRIER

1679
01:04:39,584 --> 01:04:41,987
TOAC SENTUATE AND SINCE THEY

1680
01:04:41,987 --> 01:04:44,289
WERE DEVELOPED FOR MS

1681
01:04:44,289 --> 01:04:45,557
PERRIVEERAL DEC VERSUS CENTRAL

1682
01:04:45,557 --> 01:04:46,725
DISEASE, COULD YOU COMMENT ON

1683
01:04:46,725 --> 01:04:50,662
HOW TO PROGRESS THIS AND MOVE

1684
01:04:50,662 --> 01:04:52,764
FROM -- GIVE THESE THINGS

1685
01:04:52,764 --> 01:04:53,432
PERIPHERALLY.

1686
01:04:53,432 --> 01:04:55,000
NALL RIGHT, SO, WE DON'T -- WITH

1687
01:04:55,000 --> 01:04:58,704
THE ADMINISTRATION OF THE DRUGS

1688
01:04:58,704 --> 01:05:00,973
INTRA FECALLY WAS TO DISSECT THE

1689
01:05:00,973 --> 01:05:02,107
PATHWAY MECHANISTICALLY, ALL OF

1690
01:05:02,107 --> 01:05:07,713
THE OTHER SPRMS WE GIVE THE DRUG

1691
01:05:07,713 --> 01:05:08,347
ORALLY, THEY'RE ALREADY

1692
01:05:08,347 --> 01:05:09,948
AVAILABLE AND THEY GET INTO THE

1693
01:05:09,948 --> 01:05:10,882
CENTRAL NERVOUS SYSTEM

1694
01:05:10,882 --> 01:05:11,550
BEAUTIFULLY WELL.

1695
01:05:11,550 --> 01:05:13,418
SO WE DON'T HAVE TO WORRY ABOUT

1696
01:05:13,418 --> 01:05:13,618
THAT.

1697
01:05:13,618 --> 01:05:15,754
THEY WILL GET TO THE CENTRAL

1698
01:05:15,754 --> 01:05:17,789
NERVOUS SYSTEM VERY NICELY AND

1699
01:05:17,789 --> 01:05:21,126
THEY USE FOR MULTIPLE SCLEROSIS

1700
01:05:21,126 --> 01:05:23,662
FOR THAT, SO CNS PENETRATION IS

1701
01:05:23,662 --> 01:05:27,833
NOT AN ISSUE FOR THESE DRUGS.

1702
01:05:27,833 --> 01:05:29,835
>> OKAY, WELL, THANK YOU
SO MUCH

1703
01:05:29,835 --> 01:05:32,237
DANIELA, THANK YOU FOR YOUR

1704
01:05:32,237 --> 01:05:33,572
PIONEERING WORK NTHANK YOU.

1705
01:05:33,572 --> 01:05:34,339
>> [ APPLAUSE ]

1706
01:05:34,339 --> 01:05:36,108
NAND FOR YOUR DETERMINATION TO

1707
01:05:36,108 --> 01:05:39,611
BRING YOUR CONCEPTS TO

1708
01:05:39,611 --> 01:05:41,046
TRANSLATION TO ULTIMATELY REDUCE

1709
01:05:41,046 --> 01:05:43,382
PATIENT SUFFERING.

1710
01:05:43,382 --> 01:05:43,782
>> THANK YOU SO.

1711
01:05:43,782 --> 01:05:45,217
>> THANK YOU, THANK YOU
VERY

1712
01:05:45,217 --> 01:05:46,251
MUCH EVERYONE.

1713
01:05:46,251 --> 01:05:49,354
YOU'RE NOW INVITED TO THE

1714
01:05:49,354 --> 01:05:49,788
RECEPTION OUTSIDE.

1715
01:05:49,788 --> 01:05:59,998
[ APPLAUSE ]