Role of Vascular Ion Channels in Heart Failure and Cardiovascular Diseases

描述（由申请人提供）：拟议的K 08指导职业发展奖将使我能够发展成为一个成熟的和独立的研究人员，具有血管离子通道在心力衰竭（HF）和其他与血管功能障碍相关的心血管疾病（如高血压和糖尿病）中的作用的专业知识。我是一名临床心脏病学家、心脏电生理学家，也是一名经验丰富的基础和转化研究人员，其长期目标是了解心血管疾病中血管系统的电生理重塑，以开发治疗HF和血管功能障碍的新疗法。然而，进一步的职业发展和研究培训是必要的，我达到这一目标。我与我的导师Steven马克思博士有着长期的、富有成效的关系，他是一位经验丰富的离子通道研究人员，我与他一起发表了HF中阻力血管经历血管系统电重构的发现;具体地，血管平滑肌（VSM）细胞膜电位去极化，胞浆[Ca 2 +]升高，血管大电导的表达和活性，与没有心力衰竭的小鼠相比，Ca 2+激活的钾通道（BK通道）显著减少。我计划阐明导致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。我已经安排了一个多学科的调查委员会（Donna Mancini博士、Andrew Marks博士、Paolo科隆博博士、Robert Kass博士、Shunichi Homma博士）和职业发展导师（Jaime Rubin博士），帮助我实现以下目标：（1）获得全面的基本细胞电生理学训练，（2）获得分子心脏病学的技能，以产生和表型化人类充血性心力衰竭的新小鼠模型，并研究逆转血管功能障碍和心力衰竭的可能疗法，以及（3）进行伦理研究，同时获得有效的研究报告和出版的必要技能。我计划使用在此期间获得的数据和技能来开发治疗HF和血管疾病的新疗法。

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.