Role of Vascular Ion Channels in Heart Failure and Cardiovascular Diseases

血管离子通道在心力衰竭和心血管疾病中的作用

• 批准号: 9134807
• 负责人: Elaine Y Wan
• 金额: $ 16.43万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134807
• 关键词: Admission activity; Aorta; Attenuated; Award; Blood Vessels; Blood flow; Caliber; Cardiac; Cardiac Output; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cell membrane; Cerebrum; Cessation of life; Clinical; Congestive Heart Failure; Coronary; Data; Dependence; Diabetes Mellitus; Diagnosis; Doxycycline; Echocardiography; Electrophysiology (science); Equilibrium; Ethics; Goals; Health; Heart failure; Hospitalization; Hospitals; Human; Hypertension; Image; Ion Channel; K-Series Research Career Programs; Measures; Mediating; Membrane Potentials; Mentors; Mesentery; Molecular; Molecular Profiling; Mus; Myocardial Infarction; Myocardial perfusion; Organ; Outcome; Pathway interactions; Perfusion; Peripheral Resistance; Phase; Phenotype; Post-Translational Protein Processing; Potassium Channel; Publications; Publishing; Regulation; Relaxation; Research; Research Personnel; Research Training; Resistance; Role; Serum Markers; Severities; Skeletal Muscle; Smooth Muscle Myocytes; Splanchnic Circulation; Syndrome; Systemic blood pressure; Time; Training; Transgenes; Transgenic Mice; Vascular Diseases; Vascular Smooth Muscle; Wild Type Mouse; Workload; base; career development; electrical property; experience; improved; inhibitor/antagonist; large-conductance calcium-activated potassium channels; mouse model; multidisciplinary; novel therapeutic intervention; novel therapeutics; pressure; research and development; skills; vascular bed; vasoconstriction; voltage

DESCRIPTION (provided by applicant): The proposed K08 Mentored Career Development Award will enable me to develop into an established and independent researcher with expertise on the role of vascular ion channels in heart failure (HF) and other cardiovascular diseases associated with vascular dysfunction, such as hypertension and diabetes. I am a clinical cardiologist, cardiac electrophysiologist, as well as experienced basic and translational researcher whose long-term goal is to understand the electrophysiologic remodeling of the vasculature in cardiovascular diseases to develop new therapies for the treatment of HF and vascular dysfunction. However, further career development and research training is necessary for me to reach this goal. I have a long-standing, productive relationship with my mentor, Dr. Steven Marx, an experienced ion channel researcher, with whom I published the finding that resistance vessels in HF undergo electrical remodeling of the vasculature; specifically, the vascular smooth muscle (VSM) cell membrane potential is depolarized, cytosolic [Ca2+] is elevated, and the expression and activity of vascular large conductance, Ca2+ activated potassium channels (BK channels) are markedly reduced compared to mice without heart failure. I plan to elucidate the ion channels responsible for this vascular dysfunction. The centra hypothesis of this application is that abnormal vascular ion channel activity may be one of the molecular mechanisms that causes vascular dysfunction. I have arranged a multidisciplinary board of established investigators (Dr. Donna Mancini, Dr. Andrew Marks, Dr. Paolo Colombo, Dr. Robert Kass, Dr. Shunichi Homma) and career development mentor (Dr. Jaime Rubin), to help me attain the goals of (1) obtaining comprehensive basic cellular electrophysiologic training, (2) acquiring skills in molecular cardiology to generate and phenotype new mouse models of human congestive heart failure and study possible therapies to reverse vascular dysfunction and heart failure, and (3) conducting ethical research, while acquiring the necessary skills for effective research presentation and publication. I plan to use data and skills acquired during this award to develop new therapies to treat HF and vascular disease.

描述（由申请人提供）：拟议的 K08 指导职业发展奖将使我能够发展成为一名成熟的独立研究人员，拥有血管离子通道在心力衰竭 (HF) 和与血管功能障碍相关的其他心血管疾病中的作用的专业知识，例如如高血压和糖尿病。我是一名临床心脏病学家、心脏电生理学家，也是经验丰富的基础和转化研究员，其长期目标是了解心血管疾病中脉管系统的电生理重塑，以开发治疗心力衰竭和血管功能障碍的新疗法。然而，为了实现这一目标，我需要进一步的职业发展和研究培训。我与我的导师 Steven Marx 博士有着长期、富有成效的关系，他是一位经验丰富的离子通道研究员，我与他一起发表了以下发现：心力衰竭中的阻力血管经历了脉管系统的电重塑；具体而言，与未发生心力衰竭的小鼠相比，血管平滑肌（VSM）细胞膜电位去极化，胞质[Ca2+]升高，血管大电导、Ca2+激活钾通道（BK通道）的表达和活性显着降低。我计划阐明导致这种血管功能障碍的离子通道。本申请的中心假设是血管离子通道活性异常可能是导致血管功能障碍的分子机制之一。我安排了一个由知名研究人员（Donna Mancini 博士、Andrew Marks 博士、Paolo Colombo 博士、Robert Kass 博士、Shunichi Homma 博士）和职业发展导师（Jaime Rubin 博士）组成的多学科委员会，以帮助我实现目标是 (1) 获得全面的基础细胞电生理训练，(2) 获得分子心脏病学技能，以生成人类充血性心力衰竭的新小鼠模型并对其进行表型分析，并研究逆转血管病变的可能疗法功能障碍和心力衰竭，以及（3）进行伦理研究，同时获得有效研究展示和出版的必要技能。我计划利用在该奖项期间获得的数据和技能来开发治疗心力衰竭和血管疾病的新疗法。