Myocardial Regulation of betaARK1 by Protein Kinase C

蛋白激酶 C 对 betaARK1 的心肌调节

• 批准号: 7128537
• 负责人: Shahab A Akhter
• 金额: $ 13.33万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7128537
• 关键词: G protein; G protein coupled receptor kinase; beta adrenergic receptor; beta adrenergic receptor kinase; biological signal transduction; cardiovascular disorder prevention; cell surface receptors; disease /disorder model; enzyme activity; genetically modified animals; heart failure; kinase inhibitor; laboratory mouse; molecular pathology; myocardium; northern blottings; pathologic process; protein kinase C; receptor coupling; ventricular hypertrophy; western blottings

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for development as an independent clinician-scientist. I have completed residency training in General Surgery which included a 2 year NIH-funded research fellowship in molecular cardiovascular biology. I then completed a residency program in Thoracic Surgery and am now an Assistant Professor in the Section of Cardiothoracic Surgery at the University of Cincinnati. This program will build upon my scientific foundation in G protein-coupled receptor signaling in heart disease. Arnold Schwartz, PhD will mentor my scientific and career development as he is a leader in the area of cardiac signal transduction and has an outstanding record of training young investigators. To enhance the training, Stephen B. Liggett, MD will serve as a co-mentor and is an expert in cardiac beta-adrenergic receptor (betaAR) signaling. In addition, an advisory committee of highly-regarded investigators will provide scientific and career advice. Molecular mechanisms for the transition from compensatory or adaptive myocardial hypertrophy to heart failure remain unclear. This research plan focuses on defining cross-talk between signaling pathways in the heart which are critical for the development of myocardial hypertrophy (Gq-coupled receptor signaling) and the regulation of cardiac function (betaAR signaling). The betaAR kinase (betaARK1) is the most abundant G protein-coupled receptor kinase in the heart and is critical in the regulation of betaAR signaling and cardiac function. Protein kinase C (PKC), which is activated in the development of hypertrophy following stimulation of Gq-coupled receptors, has been shown to phosphorylate and activate betaARK1 in vitro. This proposal will directly test the central hypothesis that there is cross-talk between myocardial PKC activity and betaAR signaling which occurs at the level of betaARK1 in vivo. The consequences of the actions of PKC on betaARK1 lead to the impaired betaAR signaling and cardiac function associated with ventricular hypertrophy. Based on the intellectual and scientific environment, the commitment from my Department, and support from my mentors and advisory committee, I believe the University of Cincinnati Cardiovascular Research Center provides an ideal setting for training physician-scientists to become successful independent investigators.

描述（由申请人提供）： 该提案描述了一项为期5年的发展培训计划，以作为独立的临床医生科学家。 我已经完成了一般手术的居住培训，其中包括NIH资助的2年分子心血管生物学研究奖学金。 然后，我完成了胸外科手术的居住计划，现在是辛辛那提大学心胸外科手术区的助理教授。 该程序将基于我在心脏病中G蛋白偶联受体信号传导中的科学基础。 阿诺德·施瓦茨（Arnold Schwartz）博士将指导我的科学和职业发展，因为他是心脏信号转导领域的领导者，并且拥有培训年轻调查员的出色记录。 为了增强培训，医学博士Stephen B. Liggett将担任辅助者，并且是心脏β-肾上腺素能受体（BETAAR）信号的专家。 此外，由备受瞩目的调查人员组成的咨询委员会将提供科学和职业建议。 从补偿性或适应性心肌肥大过渡到心力衰竭的分子机制尚不清楚。 该研究计划的重点是定义心脏中信号通路之间的串扰，这对于心肌肥大的发展至关重要（GQ耦合受体信号传导）和心脏功能的调节（BETAAR信号传导）。 βAR激酶（betaark1）是心脏中最丰富的G蛋白偶联受体激酶，对于调节βAR信号传导和心脏功能至关重要。 蛋白激酶C（PKC）在刺激GQ耦合受体后在肥大的发展中被激活，已显示出在体外磷酸化和激活betaark1。 该提案将直接检验中心假设，即在体内betaark1水平上发生的心肌PKC活性与βAR信号之间存在串扰。 PKC对betaark1的作用的后果导致βAR信号传导和心室肥大相关的心脏功能受损。 根据智力和科学环境，我的部门的承诺以及导师和咨询委员会的支持，我相信辛辛那提大学心血管研究中心为培训医师科学家成为成功的独立研究人员提供了理想的环境。