KATP channel expression and localization in the progression of heart failure

本申请描述了一项旨在提高申请人技能的研究和教育计划，该计划将 允许独立从事心脏疾病分子机制的研究。申请人 具有通过以前的培训获得的电生理学和生物物理学背景，但需要 分子生物学、基因转移、共聚焦显微镜和 生物信息学。这项建议是为了通过执行科学项目来提供这种培训 在多学科咨询委员会的指导下，以及课程作业和研讨会。这个 研究部分将研究心力衰竭中心脏保护的分子机制。 心血管疾病是美国主要的死亡原因，每三个成年人中就有一个受到影响，因此 这是一个巨大的公共卫生问题。心力衰竭是晚期疾病的后果， 目前在大约500万美国人中存在，预计随着人口老龄化而增加。可用 治疗方法往往不足以治疗或预防心脏病的进展。新出现的数据表明 心肌保护性ATP敏感钾(KATP)通道的膜表达调控 在心脏对应激适应中的重要作用。初步结果表明，钙/钙调蛋白依赖于 蛋白激酶II(CaMKII)抑制增加KATP通道表面与耐药性相关的表达 到了缺血性损伤。初步结果也表明运输蛋白Ankyrin-B在KATP中的作用 通道膜定位。目标#1将定义KATP通道膜的调节机制 CaMKII在正常和衰竭心脏中的表达水平，而Aim#2将决定其在膜上的作用 Ankyrin-B在正常和衰竭心脏中对心肌细胞KATP通道的定位总而言之，这些目标 将阐明KATP通道表达的动态变化、CaMKII信号转导与 锚蛋白-B膜的定位。基因调控的分子机制的建立 KATP通道膜的表达和定位将确定潜在的治疗途径 心衰机械和电功能障碍的预防和有针对性的干预。这是科学的 与职业发展计划相配合的计划将为申请者提供获得 作为一名成功的内科科学家，她需要其他技能来定位自己的独立职业生涯。

This application describes a program of research and education to enhance the applicant's skills that will permit an independent career in investigation of molecular mechanisms of cardiac disease. The applicant has a background in electrophysiology and biophysics acquired through previous training, but requires additional theory and methodology in molecular biology, gene transfer, confocal microscopy and bioinformatics. This proposal is tailored to provide such training through execution of the scientific project under mentorship of a multidisciplinary advisory committee, as well as course work and seminars. The research component will investigate molecular mechanisms of cardioprotection in heart failure. Cardiovascular disease is the leading cause of mortality in the United States with 1 in 3 adults affected, thus presenting an enormous public health concern. Heart failure is the consequence of advanced disease and is present in approximately 5 million Americans, expected to increase as the population ages. Available therapies are often inadequate to treat or prevent progression of heart disease. Emerging data suggest membrane expression regulation of the cardioprotective ATP-sensitive potassium (KATP) channel plays a significant role in cardiac adaptation to stress. Preliminary results indicate that Ca2+/calmodulin dependent protein kinase II (CaMKII) inhibition increases KATP channel surface expression associated with resistance to ischemic injury. Preliminary results also indicate a role for the trafficking protein ankyrin-B in KATP channel membrane localization. Aim #1 will define the mechanism for regulation of KATP channel membrane expression level by CaMKII in normal and failing hearts while Aim #2 will determine the role in membrane localization of cardiomyocyte KATP channels by ankyrin-B in normal and failing hearts. Together, these aims will elucidate the relationship between the dynamics of KATP channel expression, CaMKII signaling and ankyrin-B membrane localization. Establishment of the molecular mechanisms underlying the regulation of KATP channel membrane expression and localization will identify potential therapeutic avenues for prevention and targeted interventions of mechanical and electrical dysfunction in heart failure. This scientific program in concert with the career development plan will provide the opportunity for the applicant to acquire additional skills needed to position her for an independent career as a successful physician-scientist.