Role of Vascular Ion Channels in Heart Failure and Cardiovascular Diseases

描述(由申请人提供)：建议的K08导师职业发展奖将使我发展成为一名成熟的独立研究员，拥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)中的作用方面的专业知识。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翻译研究人员，其长期目标是了解心血管疾病中血管的电生理学重构，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，进一步的职业发展和研究培训是必要的。我与我的导师史蒂文·马克思博士有着长期的富有成效的合作关系，他是一位经验丰富的离子通道研究员，我与他一起发表了这一发现，即与非心力衰竭小鼠相比，心力衰竭小鼠的阻力血管经历了血管系统的电重构；具体地说，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、钙激活钾通道(BK通道)的表达和活性显著降低。我计划阐明导致这种血管功能障碍的离子通道。这一应用的中心假设是，异常的血管离子通道活动可能是导致血管功能障碍的分子机制之一。我已经安排了一个由知名研究人员(唐娜·曼奇尼博士、安德鲁·马克斯博士、保罗·科伦坡博士、罗伯特·卡斯博士、Homma Shunichi博士)和职业发展导师(Jaime Rubin博士)组成的多学科委员会，以帮助我实现以下目标：(1)获得全面的基本细胞电生理训练，(2)掌握分子心脏病学技能，以产生和表型新的人类充血性心力衰竭小鼠模型，并研究扭转血管功能障碍和心力衰竭的可能疗法，(3)进行伦理研究，同时掌握有效进行研究陈述和发表所需的技能。我计划使用在这个奖项中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。

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.