KATP channel expression and localization in the progression of heart failure

KATP 通道在心力衰竭进展中的表达和定位

• 批准号: 7623882
• 负责人: Denice Hodgson-Zingman
• 金额: $ 12.71万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-16 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623882
• 关键词: Adult; Advisory Committees; Affect; Age; American; Ankyrins; Arrhythmia; Arts; Bioinformatics; Biology; Biophysics; Calcium/calmodulin-dependent protein kinase; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiovascular Diseases; Cells; Cellular Stress; Cessation of life; Characteristics; Complement; Confocal Microscopy; Congestive Heart Failure; Data; Development; Development Plans; Disease Progression; Education; Electrons; Electrophysiology (science); Functional disorder; Gene Transfer; Growth; Heart; Heart Diseases; Heart failure; Image; Impairment; Incidence; Injury; Intervention; Investigation; Ion Channel; Iowa; Left; Mechanics; Membrane; Membrane Protein Traffic; Mentorship; Methodology; Molecular; Molecular Biology; Myocardial; Phosphorylation; Physicians; Play; Population; Positioning Attribute; Potassium; Prevention; Preventive; Process; Public Health; Publishing; Regulation; Research; Research Personnel; Resistance; Resources; Risk; Role; Scanning; Scientist; Signal Transduction; Stress; Surface; Techniques; Therapeutic; Therapeutic Intervention; Training; Translations; United States; Universities; Ventricular; Work; advanced disease; calmodulin-dependent protein kinase II; career; career development; mortality; multidisciplinary; novel; novel therapeutic intervention; prevent; programs; protein transport; skills; stressor; theories

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.

该申请描述了一项研究和教育计划，旨在提高申请人的技能，这将 允许独立从事心脏病分子机制研究。申请人 具有通过之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、共焦显微镜和 生物信息学。该提案旨在通过执行科学项目来提供此类培训 在多学科咨询委员会以及课程工作和研讨会的指导下。这 研究部分将研究心力衰竭心脏保护的分子机制。 心血管疾病是美国死亡的主要原因，三分之一的成年人受到影响，因此 提出了巨大的公共卫生问题。心力衰竭是晚期疾病的结果， 大约有 500 万美国人存在这种情况，预计随着人口老龄化而增加。可用的 疗法通常不足以治疗或预防心脏病的进展。新兴数据表明 心脏保护性 ATP 敏感钾 (KATP) 通道的膜表达调节发挥着重要作用 在心脏对应激的适应中发挥着重要作用。初步结果表明 Ca2+/钙调蛋白依赖性 蛋白激酶 II (CaMKII) 抑制会增加与耐药性相关的 KATP 通道表面表达 至缺血性损伤。初步结果还表明运输蛋白锚蛋白 B 在 KATP 中发挥作用 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，而目标 #2 将决定在膜中的作用 正常和衰竭心脏中锚蛋白 B 定位心肌细胞 KATP 通道。这些目标共同实现 将阐明 KATP 通道表达动态、CaMKII 信号传导和 锚蛋白-B 膜定位。调控分子机制的建立 KATP 通道膜表达和定位将确定潜在的治疗途径 心力衰竭机械和电功能障碍的预防和有针对性的干预。这种科学的 与职业发展计划相结合的计划将为申请人提供获得知识的机会 需要额外的技能才能让她成为一名成功的医师科学家，获得独立的职业生涯。