The purpose of this application is to create a research and training program which will allow Dr. Lanfear to develop into an independent clinician-scientist with translational research projects focused on cardiovascular pharmacogenetics. The proposed program will accomplish this goal through completion of the research sroject, technical skills training, didactic coursework focused on genome-wide techniques, and outstanding mentorship. The overall strengths of the proposal are further supported by the quality of the applicant and the relevance and scientific merit of the research project. The applicant has clinical expertise in heart failure [HF), experience in genotyping, advanced training in study design and statistics (culminating in an M.S.), and has shown focus and motivation through successfully completing projects and publishing the results in reputable journals. He would greatly benefit from the proposed coursework in array-based genomic techniques as well as the skills gained via execution of the research project. The research project will enhance his technical skills, allow mentoring, and will generate data for publication and justification of future experiments. It focuses on HF which continues to be an enormous public health problem despite many advances in pharmacotherapy over the past 25 years. There are currently insufficient tools to guide the optimal selection of drug therapy for individuals. The expansion of human genomic information has led to exciting new opportunities for pharmacogenetics to improve drug therapy. One of the most exciting new areas in HF is the natriuretic peptide system. B-type Natriuretic Peptide (BMP) has diagnostic and prognostic importance in HF and is a commercially available therapeutic agent for acute HF exacerbations. Despite its beneficial effects, BMP therapy has several limitations; it is intravenous, expensive, and has potential toxicities. The goal of this project is to define genetic predictors of the efficacy and toxicity of intravenously administered BMP. A candidate gene approach will be taken and sequence data will be correlated with pharmacokinetic, pharmacodynamic, and clinical response parameters. As a mechanistic validation the association of sequence variants with expression level of the candidate genes and quantity of protein products will be assessed in human kidney tissue samples. The overall program will not only define functional predictive variants, but will advance the candidate's career while setting the ground work for follow-up studies of pharmacogenetically directed BNP therapy. (End of Abstract) ? ? ?
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