Determinants of drug action can be broadly divided into two areas: pharmacokinetics (Does the drug research the target site?) And pharmacodynamics (Once the drug reaches its target site, does the drug bind to its receptor and influence that receptor's signaling and action?). This UCSD/Celera pharmacogenomics center will probe pharmacodynamic determinants of human drug responses. Our focus is human autonomic cardiovascular drug responses in both the systemic and pulmonary circulations. To achieve this focus on the pharmacodynamics of autonomic cardiovascular responses, we have developed an initial phenotyping strategy to emphasize regional (rather than systemic) vascular responses, so as to remove pharmacokinetic and baroreflex variables from their confounding influence, and thereby to isolate and focus upon pharmacodynamic (receptor, post-receptor, and effector) determinants of drug responses. Phenotyping projects 1-> generate information and samples which flow systematically through 7 cores (A-> G), to achieve center goals. The regional responses are characterized in the pulmonary (Phenotyping project 1), renal (Phenotyping project 2), forearm (Phenotyping project 3) and post-synaptic (Phenotyping projects 2&4) responses are studied. This center will evaluate both diagnostic (Phenotyping projects 1->) and therapeutic )Phenotyping projects 1&2; Core G) drug responses. Diagnostic drug responses will allow us to more effectively and """"""""cleanly"""""""" probe receptor and post-receptor signaling, thereby providing rigorous pharmacodynamic insights to be applied later to therapeutic drug responses in humans. Diagnostic responses should allow definition of which SNP alleles contribute to variation in signaling in a particular pathway. We hypothesize that agonist responses, obtained under carefully defined circumstances in regional circulatory beds (pulmonary, renal, forearm, hand), will lead to the discovery of associated SNP alleles which will ultimately yield diagnostic tools to predict therapeutic drug responses (in particular, for antagonists at the same receptors). SNPs will be productive UCSD collaboration with Celera Genomics, a pioneer in large-scale human genome sequencing. The functional significance of discovered SNP alleles will be verified in vitro (Cores D&E) and in experimental organisms (Core F). Finally, such SNP alleles will then be tested in human drug response trials (Core G) to answer the question: Does SNP stratification predict therapeutic drug response in large, prospective, randomized, controlled clinical trials?
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