NIH VideoCast - Matching Complex Biomarkers to Drugs Using HistoReceptomic Signatures

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Matching Complex Biomarkers to Drugs Using HistoReceptomic Signatures

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Air date:	Wednesday, November 13, 2013, 2:00:00 PM Time displayed is Eastern Time, Washington DC Local
Views:	Total views: 388 (50 Live, 338 On-demand)
Category:	Special
Runtime:	00:56:38
Closed captioning:	Check box to display CC outside of the video Note: You can drag the captioning window around and resize it
Description:	NLM Informatics Lecture Series Personalized medicine theorizes that individuals suffering from complex diseases exhibit unique genomic activity profiles to which drug treatments can be matched. Unfortunately, most drugs were discovered phenotypically and have unknown and complex mechanisms of action, making their matching to personalized profiles difficult. We derived a novel molecular signature for drug action by integrating a large set of drug:receptor affinities across the human proteome with receptor gene-expression data in human tissues. The resulting HistoReceptOmic signatures can potentially be used to match diagnostic complex biomarkers of disease to drugs. To demonstrate the utility of the approach we applied it to a psychiatric disease, schizophrenia, for which drug action is not well understood. Specifically, we used this approach to characterize the atypical pharmacologic action (“atypia”) of the antipsychotic drug clozapine, i.e. its beneficial effects that the typical antipsychotic drug chlorpromazine does not exhibit. Our results suggest that the common antipsychotic effects of clozapine and chlorpromazine derive most strongly from the drug’s action on 5-HT2a and 5-HT2c receptors in the prefrontal cortex and caudate nucleus respectively, histamine H1 receptors in the superior cervical ganglion, and muscarinic acetylcholine M3 receptors in the prefrontal cortex. In contrast, targets exclusive to clozapine are dopamine D4 receptors in pineal gland, and muscarinic acetylcholine M1 receptors in prefrontal cortex. These results provide novel perspectives on the mechanism of action of antipsychotics as well as the atypical action of clozapine in schizophrenia. Most importantly, the HistoReceptomics approach might be used generally to match complex biomarkers of disease to drugs or drug-combinations.

NLM Title:	Matching complex biomarkers to drugs using historeceptomic signatures / Timothy Cardozo.
Author:	Cardozo, Timothy. National Institutes of Health (U.S.),
Publisher:
Abstract:	(CIT): Personalized medicine theorizes that individuals suffering from complex diseases exhibit unique genomic activity profiles to which drug treatments can be matched. Unfortunately, most drugs were discovered phenotypically and have unknown and complex mechanisms of action, making their matching to personalized profiles difficult. We derived a novel molecular signature for drug action by integrating a large set of drug:receptor affinities across the human proteome with receptor gene-expression data in human tissues. The resulting HistoReceptOmic signatures can potentially be used to match diagnostic complex biomarkers of disease to drugs. To demonstrate the utility of the approach we applied it to a psychiatric disease, schizophrenia, for which drug action is not well understood. Specifically, we used this approach to characterize the atypical pharmacologic action ("atypia") of the antipsychotic drug clozapine, i.e. its beneficial effects that the typical antipsychotic drug chlorpromazine does not exhibit. Our results suggest that the common antipsychotic effects of clozapine and chlorpromazine derive most strongly from the drug"s action on 5-HT2a and 5-HT2c receptors in the prefrontal cortex and caudate nucleus respectively, histamine H1 receptors in the superior cervical ganglion, and muscarinic acetylcholine M3 receptors in the prefrontal cortex. In contrast, targets exclusive to clozapine are dopamine D4 receptors in pineal gland, and muscarinic acetylcholine M1 receptors in prefrontal cortex. These results provide novel perspectives on the mechanism of action of antipsychotics as well as the atypical action of clozapine in schizophrenia. Most importantly, the HistoReceptomics approach might be used generally to match complex biomarkers of disease to drugs or drug-combinations.
Subjects:	Biomarkers, Pharmacological Drug Therapy--methods Pharmacogenetics--methods Precision Medicine--methods Schizophrenia--drug therapy
Publication Types:	Lecture Webcast

NLM Classification:	QV 38.5
NLM ID:	101622757
CIT Live ID:	13272
Permanent link:	https://videocast.nih.gov/watch=13272

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