Atrial Fibrillation Susceptibility Due to Genetic Variation at Chromosome 4q25

 描述(申请人提供)：应聘者：舒梅克博士是一位心脏电生理学家，在以患者为中心的研究方面拥有高级学位(临床调查理学硕士)。他于2014年7月加入教职员工，担任内科科学家，计划从事研究心律失常的药物基因组学的职业。Shoemaker博士的短期目标是了解常见基因变异导致房颤(AF)的电生理(EP)机制，并调整房颤治疗的临床反应。在这个职业发展奖的五年时间里，他计划加强对临床药理学和药物科学、遗传学、数量性状分析方法和临床试验设计的理解。Shoemaker博士的长期目标是建立一个研究计划，专注于开发个性化和基于药物基因组学的房颤治疗方法。他的职业发展计划和补充研究建议的目标是发展技能和产生初步数据，以通过R01赠款机制成功竞争独立资金。 环境：范德比尔特大学既是美国国立卫生研究院临床和翻译科学奖(CTSA)计划的协调中心，也是药物基因组学研究网络(PGRN)的心律失常治疗药物基因组学(PAT)节点的牵头站点，非常适合为Shoemaker博士提供临床研究和药物基因组学研究方法方面的交叉培训。他拥有一支成熟的导师团队，拥有心律失常遗传学、药物基因组学以及临床试验设计和实施方面的综合专业知识。Dawood Darbar博士是一位临床电生理学家，在房颤的人类遗传学方面拥有全国领先地位，同时也是范德比尔特心律失常服务中心主任。迈克尔·斯坦博士是一名具有心血管药物基因组学专业知识的临床试验专家，曾任临床和翻译研究科学家发展助理主任。罗登博士是负责个性化医学的助理副校长，并担任联邦政府资助的几个大型项目的首席研究员，这些项目侧重于药物基因组学的实施，包括PGRN的PAT节点。这三位导师都致力于舒梅克博士的职业发展，并有成功指导年轻调查人员的记录。 研究：我们提出了两个特定的目标，试图定义EP机制(S)，通过该机制，染色体4q25基因座上的常见遗传变异有助于房颤的易感性并调节对房颤治疗的反应。在接受消融治疗的房颤患者中，将使用标准化的心内电测量数据进行表型分析。特异的目标集中在染色体4q25上的单核苷酸多态(SNPs)，这些SNPs被GWAS鉴定为与房颤密切相关。它们被怀疑是附近基因PITX2(配对的同源结构域转录因子2)的转录调节因子，在转基因小鼠中已被发现调节肺静脉(PV)心肌袖子的发育-房颤发病的关键结构，并通过不利的电和结构重构导致心房电生理学的顺心律失常改变。虽然我们已经证明，4q25的房颤风险等位基因预测了房颤消融治疗的临床反应受损，并调节了对抗心律失常药物的反应，但这些观察到的潜在机制(S)仍不清楚。在具体目标1中，我们试图进一步了解4q25风险等位基因携带者对PV心肌袖大小和心房不应期变化的影响。这些发现不仅将促进我们对4q25风险等位基因携带者如何对分离PV心肌袖子(消融)做出反应的理解，还将促进我们对特定的AAD治疗的反应，AAD治疗通过减缓心房复极或传导速度来调节其效果。在特定的目标2中，我们特别关注房颤消融，通过检验4q25风险等位基因携带者在接受房颤消融后由于非PV介导的房颤来源而更有可能复发房性快速心律失常的假设。这一发现将为测试基于4q25基因的个性化房颤消融策略的试验提供依据。这些目标旨在为Shoemaker博士提出未来的临床试验，调查房颤消融治疗的个性化和基于药物基因组学的AAD治疗方法来治疗这种常见和病态的疾病。

 DESCRIPTION (provided by applicant): Candidate: Dr. Shoemaker is a cardiac electrophysiologist with an advanced degree in patient-oriented research (Master of Science in Clinical Investigation). He joined faculty as a physician-scientist in July 2014 with plans to pursue a career studying the pharmacogenomics of cardiac arrhythmias. Dr. Shoemaker's shortterm goal is to understand the electrophysiologic (EP) mechanisms by which common genetic variants lead to atrial fibrillation (AF) and modulate clinical response to AF therapies. During the five years of this career development award, he plans to strengthen his understanding of clinical pharmacology and drug science, genetics, methods for quantitative trait analysis, and clinical trial design. Dr. Shoemaker's long-term goal is to establish a researc program focused on the development of personalized and pharmacogenomics-based approaches to AF therapy. The goal of his career development plan and complementary research proposal is to develop the skills and generate preliminary data to successfully compete for independent funding through R01 grant mechanisms. Environment: As both the coordinating center of the NIH's Clinical and Translational Science Award (CTSA) program, and lead site for the Pharmacogenomics of Arrhythmia Therapy (PAT) node of the Pharmacogenomics Research Network (PGRN), Vanderbilt University is ideally suited to provide Dr. Shoemaker cross-training in clinical investigation and pharmacogenomics research methods. He has a well established mentorship team with combined expertise in the genetics of arrhythmias, pharmacogenomics, and clinical trial design and implementation. Dr. Dawood Darbar is a clinical electrophysiologist and established physician-scientist with national leadership recognition in the human genetics of AF, and Director of the Vanderbilt Arrhythmia Service. Dr. C. Michael Stein is a clinical trialist with expertise in cardiovascular pharmacogenomics and previously Assistant Dean for Clinical and Translational Research Scientist Development. Dr. Roden is Assistant Vice Chancellor for Personalized Medicine and serves as Principal Investigator for several large federally-funded projects focused on implementation of pharmacogenomics including the PAT node of the PGRN. All three mentors are committed to Dr. Shoemaker's career development and have a track record of successfully mentoring young investigators. Research: We propose two Specific Aims that seek to define the EP mechanism(s) by which common genetic variants at the chromosome 4q25 locus contribute to AF susceptibility and modulate response to AF therapies. Phenotyping will be performed using standardized collection of intracardiac EP measurements in patients with AF undergoing ablation. The Specific Aims focus on single nucleotide polymorphisms (SNPs) at chromosome 4q25 that were identified by GWAS to be strongly associated with AF. They are suspected to be transcriptional regulators of a nearby gene, PITX2 (paired-like homeodomain transcription factor 2), which in transgenic mice has been found to regulate development of the pulmonary vein (PV) myocardial sleeve - a critical structure in AF pathogenesis, and result in pro-arrhythmic changes in atrial electrophysiology through adverse electrical and structural remodeling. While we have demonstrated that AF risk alleles at 4q25 predict an impaired clinical response to treatment with AF ablation and modulate response to antiarrhythmic drugs (AADs), the underlying mechanism(s) for these observations remains unknown. In Specific Aim 1, we seek to further our understanding of the effect of 4q25 risk allele carriers on PV myocardial sleeve size and changes in atrial refractoriness. These findings will not only advance our understanding of how 4q25 risk allele carriers respond to isolation of the PV myocardial sleeves (ablation) but also to specific AAD therapies, which mediate their effect by slowing either atrial repolarization or conduction velocity. In Specific Aim 2 we focus specifically on AF ablation by testing the hypothesis that 4q25 risk allele carriers who undergo AF ablation are more likely to have recurrence of atrial tachyarrhythias due to non-PV mediated AF sources. This finding would inform trials testing personalized AF ablation strategies based on 4q25 genotype. These Aims are designed to provide preliminary data for Dr. Shoemaker to propose future clinical trials investigating both personalization of AF ablation therapy and a pharmacogenomics-based approach to AAD therapy for this common and morbid condition.