Functional Implications of Caveolae-Localized Myocardial sGC in Heart Failure

描述（由申请人提供）：本提案描述了一个全面的5年培训计划，用于分子和细胞心脏病学的学术临床科学家的职业发展。主要研究者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，临床亚专业为晚期心力衰竭和心脏移植。现在是坦普尔大学医学院的助理教授，PI寻求分子和细胞电生理学以及综合心脏生理学的额外研究培训。PI的长期职业目标是获得心力衰竭病理生理学的原始见解，确定药物开发的新靶点，并最终将创新疗法引入临床护理。她更直接的目标是成为一名心肌细胞生物学家。候选人将研究的作用 一氧化氮（NO）受体可溶性鸟苷酸环化酶（sGC）在心力衰竭中异常NO信号传导的病理生理学中在心肌细胞小窝微区内。她将在心脏生理学家Steven R.豪泽博士，生理学系主任和心血管研究中心主任，并共同指导的小窝生物学家维克托里佐博士，解剖学和细胞生物学副教授。一个由高级研究人员和医生科学家组成的委员会将提供科学和职业建议。 PI制定了一项研究策略，以确定小窝定位sGC的丢失有助于心脏肥大中NO和环磷酸鸟苷（cGMP）的病理信号传导的机制。PI将结合遗传、分子、细胞、免疫组织化学、电生理、功能和蛋白质组学方法：1）确定小窝定位的心肌sGC的功能意义; 2）表征与病理性肥大相关的肌细胞小窝NO信号传导的分子细节; 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都至关重要。候选人还将通过选择课程，研讨会，国家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计划的重点临床活动来加强她的职业发展。该K 08的研究结果有望为心力衰竭中异常NO信号传导的病理生理学提供新的见解，促进对肌细胞小窝微域的理解，并对心力衰竭治疗的新药开发产生积极影响。在奖励期结束时，PI将准备好作为一名独立的R 01资助的临床科学家开展职业生涯，并将在K 08期间获得的研究技能应用于研究心力衰竭病理生理学基础上的肌细胞信号传导的其他微域。

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.