Pharmacogenetics/pharmacogenomics is a research field aimed at helping to describe the genetic contribution to variability in drug efficacy and toxicity. The focus of the candidate?s research program is to determine the impact of beta-adrenergic receptor (betaAR) polymorphisms on drug response and cardiovascular disease. This broad research objective will be carried out through several studies. The first set of studies is focused in hypertension (HTN), which aim to test the hypotheses that the betaAR genes: a) are associated with HTN; b) are disease modifying in HTN, with a particular focus on the nocturnal blood pressure decline causing individuals to be either nocturnal """"""""dippers"""""""" or """"""""nondippers""""""""; and c) are important determinants of the antihypertensive response to beta-blockers. The latter aim will be tested in a small population, with focus on the blood pressure, and also through a pharmacogenetic substudy of the INVEST trial, a 22,000 patient outcomes trial in patients with hypertension and documented ischemic heart disease. The second group of studies focus on beta-blocker pharmacogenetics in heart failure. Beta-blockers have been recently documented to prolong survival and slow disease progression in heart failure patients. These outcome benefits are thought to be associated with the """"""""reverse remodeling effect"""""""" of the beta-blockers on the left ventricle (LV), which result in increases in ejection fraction, reductions in LV wall thickness and mass, and returning the ventricle to a more ellipitical shape. Despite these clear benefits, beta-blockers must be used cautiously during the titration phase to avoid worsening of heart failure, specifically, starting with very low doses, with close monitoring and cautious dose titration. These studies are focused on testing the hypotheses that certain polymorphisms of the beta1AR are associated with relatively poor initial tolerability of beta-blockers, and also with the most dramatic effects of """"""""reverse remodeling"""""""" of the left ventricle. Additional patient-oriented research studies that will be conducted as part of this research career award include a study of dobutamine pharmacogenetics, and associations between the PAR genes and obesity or coronary microvascular dysfunction. The proposed studies are important because they will enhance our understanding of the genetic basis of various cardiovascular diseases, and will provide insight into genetic factors that influence response to drugs that act at the betaAR. The pharmacogenetic studies are significant in that they may provide information that will allow the drugs of interest to be targeted to the patients most likely to derive the greatest benefit from such therapy, thus leading to better individualization of therapy, and improved patient outcomes. These studies are also important as they provide excellent research training opportunities for clinicians. The proposed Research Career Award is important to the candidate?s career development in that it will provide sufficient protected time for the candidate to successfully complete the ongoing and planned studies described herein, will enhance the training of fellows in the emerging area of pharmacogenomics, and will allow for the continued growth of the candidate?s patient-oriented research program.
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