Pharmacogenetics of the B-type Natriuretic Peptide Pathway

描述（由申请人提供）：本申请的目的是创建一个研究和培训计划，使Lanfear博士能够发展成为一个独立的临床医生和科学家，专注于心血管药物遗传学的转化研究项目。该计划将通过完成研究项目、技术技能培训、以全基因组技术为重点的教学课程以及出色的指导来实现这一目标。申请人的素质以及研究项目的相关性和科学价值进一步支持了提案的整体优势。申请人具有心力衰竭（HF）的临床专业知识，基因分型经验，研究设计和统计方面的高级培训（最终获得硕士学位），并且通过成功完成项目并在知名期刊上发表结果显示出专注和动力。他将从拟议的基于阵列的基因组技术课程以及通过执行研究项目获得的技能中受益匪浅。该研究项目将提高他的技术技能，允许指导，并将为发表和证明未来的实验产生数据。它的重点是心衰，尽管在过去25年中药物治疗取得了许多进展，但心衰仍然是一个巨大的公共卫生问题。目前没有足够的工具来指导个人药物治疗的最佳选择。人类基因组信息的扩展为药物遗传学改善药物治疗带来了令人兴奋的新机遇。心衰中最令人兴奋的新领域之一是利钠肽系统。b型利钠肽（BMP）在心衰诊断和预后中具有重要意义，是一种市售的心衰急性加重治疗剂。尽管其有益的效果，BMP治疗有几个局限性；它是静脉注射的，价格昂贵，并且有潜在的毒性。该项目的目标是确定静脉注射BMP的疗效和毒性的遗传预测因子。将采用候选基因方法，序列数据将与药代动力学、药效学和临床反应参数相关联。作为一种机制验证，序列变异与候选基因表达水平和蛋白质产物数量的关联将在人类肾脏组织样本中进行评估。整个项目不仅将定义功能预测变异，而且将推进候选人的职业生涯，同时为药理学指导的BNP治疗的后续研究奠定基础。（摘要结束）

DESCRIPTION (provided by applicant): 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)