Functional Implications of Caveolae-Localized Myocardial sGC in Heart Failure

描述(由申请者提供)：本建议书描述了一项为期5年的综合性培训计划，旨在培养分子和细胞心脏病学方面的临床科学家。这位首席研究员在约翰·霍普金斯医院完成了心血管医学的博士后临床和研究培训，并在晚期心力衰竭和心脏移植方面进行了临床子专业。现在是坦普尔大学医学院的助理教授，PI寻求在分子和细胞电生理学以及综合心脏生理学方面的额外研究培训。PI的长期职业目标是在心力衰竭的病理生理学方面获得原创性的见解，确定药物开发的新靶点，并最终将创新疗法带到临床护理中。她更直接的目标是将自己确立为一名心肌细胞生物学家。候选人将研究 一氧化氮(NO)受体在心力衰竭时NO信号异常的病理生理过程中，心肌细胞小凹微区内的可溶性鸟苷酸环化酶(SGC)。她将在心脏生理学家、生理学系主任兼心血管研究中心主任史蒂文·R·豪泽博士和小窝生物学家、解剖学和细胞生物学副教授维克托·里佐的共同指导下进行这项研究。一个由资深研究人员和内科科学家组成的委员会将提供科学和职业建议。PI已经制定了一项研究策略，以确定小窝定位的sGC丢失在心肌肥厚中参与NO和环鸟苷单磷酸(CGMP)病理信号转导的机制。结合遗传学、分子、细胞、免疫组织化学、电生理、功能和蛋白质组学方法，PI将：1)确定小凹定位的心肌sGC的功能意义；2)表征与病理性肥大相关的心肌细胞小凹NO信号的分子细节；3)确定sGC小窝定位的机制。她将通过学习心肌细胞电生理学、生理学和功能蛋白质组学技术来补充她的分子和细胞生物学研究技能-所有这些对心肌细胞生物学家来说都是至关重要的。候选人还将通过精选课程、研讨会、国内和国际科学研讨会以及坦普尔大学医院高级心力衰竭和移植项目的重点临床活动来促进她的职业发展。K08的研究结果有望为心力衰竭中NO信号异常的病理生理学提供新的见解，促进对肌小窝微域的理解，并积极推动心力衰竭治疗新药的开发。到获奖期结束时，PI将做好准备，开始作为一名独立的、由R01资助的临床科学家的职业生涯，并将应用在K08期间获得的研究技能来研究心力衰竭病理生理学基础上的其他心肌细胞信号微域。

DESCRIPTION (provided by applicant): This proposal describes a comprehensive 5-year training program for the career development of an academic clinician scientist in molecular and cellular cardiology. The principal investigator completed post- doctoral clinical and research training in Cardiovascular Medicine with clinical subspecialization in Advanced Heart Failure and Cardiac Transplantation at Johns Hopkins Hospital. Now an Assistant Professor at Temple University School of Medicine, the PI seeks additional research training in molecular and cellular electrophysiology and integrative cardiac physiology. The PI's long-term career goals are to gain original insight in the pathophysiology of heart failure, to identify novel targets for drug development, and to ultimately bring innovative therapies to clinical care. Her more immediate goals are to establish herself as a cardiac myocyte biologist. The candidate will study the role of the nitric oxide (NO) receptor soluble guanylyl cyclase (sGC) within the caveolae microdomain of cardiac myocytes in the pathophysiology of abnormal NO signaling in heart failure. She will pursue this research under the primary mentorship of cardiac physiologist Steven R. Houser, PhD, Chairperson of the Department of Physiology and Director of the Cardiovascular Research Center, and co-mentorship of caveolae biologist Victor Rizzo, PhD, Associate Professor of Anatomy and Cell Biology. A committee of senior researchers and physician-scientists will provide scientific and career advice. The PI has formulated a research strategy to determine the mechanism by which the loss of caveolae- localized sGC contributes to the pathologic signaling of NO and cyclic guanosine monophosphate (cGMP) in cardiac hypertrophy. Using a combination of genetic, molecular, cellular, immunohistochemical, electrophysio- logical, functional, and proteomic approaches, the PI will: 1) determine the functional implications of caveolae- localized myocardial sGC; 2) characterize the molecular details of myocyte caveolae NO signaling relevant to the pathologic hypertrophy; and 3) determine the mechanism of sGC caveolae-localization. She will complement her molecular and cell biology research skills by learning techniques in cardiac myocyte electrophysiology, physiology, and functional proteomics--- all of which are vital to a cardiac myocyte biologist. The candidate will also enhance her career development with select coursework, seminars, national and international scientific symposia, and focused clinical activity in the advanced heart failure and transplantation program at Temple University Hospital. Research findings of this K08 are expected to provide new insights to the pathophysiology of abnormal NO signaling in heart failure, advance the understanding of the myocyte caveolae microdomain, and positively impact novel drug development for heart failure therapy. By the end of the award period, the PI will be well poised to launch a career as an independent, R01-funded clinician scientist and will apply the research skills obtained during the K08 towards studying other microdomains of myocyte signaling underlying the pathophysiology of heart failure.