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: 7451226
• 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/7451226
• 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; Disease Progression; Disruption; 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; calmodulin-dependent protein kinase II; career; intracellular protein transport; mortality; multidisciplinary; novel; novel therapeutics; 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.

本申请描述了一项研究和教育计划，以提高申请人的技能， 允许在心脏病的分子机制的调查独立的职业生涯。申请人 具有通过先前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专门为通过执行科学项目提供这种培训而制定的 在一个多学科咨询委员会的指导下，以及课程和研讨会。的 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，每3名成年人中就有1人受到影响， 引起了巨大的公共卫生问题心力衰竭是晚期疾病的后果， 目前约有500万美国人，预计将随着人口老龄化而增加。可用 治疗通常不足以治疗或预防心脏病的进展。新数据表明 心肌保护性ATP敏感性钾通道（KATP）的膜表达调节在心肌保护中起着重要作用。 在心脏适应应激中的重要作用。初步结果表明，Ca 2 +/钙调素依赖性 蛋白激酶II（CaMKII）抑制增加与耐药性相关的KATP通道表面表达 缺血性损伤初步结果还表明，运输蛋白锚蛋白-B在KATP中的作用 通道膜定位目的#1将定义KATP通道膜的调节机制 在正常和衰竭的心脏中，CaMK II的表达水平，而目标#2将确定膜中的作用。 在正常和衰竭的心脏中通过ankrex-B定位心肌细胞KATP通道。总之，这些目标 将阐明KATP通道表达、CaMKII信号传导和 抗-B膜定位。建立调控的分子机制 KATP通道膜表达和定位将确定潜在的治疗途径， 心力衰竭中机械和电功能障碍的预防和针对性干预。这一科学 与职业发展计划相一致的计划将为申请人提供获得 需要额外的技能，定位她作为一个成功的物理学家，科学家的独立职业生涯。