PHARMACOGENETICS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Investigate how neurotransmitters released by sympathetic nerve endings control vascular responses and whether particular genotypes in individuals can predict the response to neurotransmitters. To better understand why individuals differ from one another in their response to neurotransmitters emerging from sympathetic nerve terminals. Humans differ among themselves in their responses to medications. The basis for such inter-individual differences in drug responses is not well understood. In this proposal, we will carefully characterize the responses to neurotransmitters in neurotransmitter-like drugs, representing compounds released from sympathetic nerve endings and impinging upon nerves or blood vessels in the circulation. We will carefully characterize such responses to the neurotransmitters now known to be released from sympathetic nerve endings, including catecholamines and nuropeptides. We characterize these responses in such local vascular beds as the hand (through the dorsal hand vein). In this way, we can isolate drug responses, focusing on those that occur at the receptor or in the downstream signaling pathway and effector responses to the drug. Thus, we eliminate the influence of such systemic factors as absorption, distribution, disposition, excretion and half-life. We also evaluate autonomic responses (blood pressure, heart rate, catecholamines), in human subjects. By obtaining a blood sample for preparation of genomic DNA, and by genotyping individuals at loci likely to influence the drug responses (such as the receptor and post-receptor signaling machinery impinged upon by the drug), we will better understand whether particular genes influence drug responses or autonomic physiology (as mediated by receptor polymorphisms) in humans.