Myocardial Regulation of betaARK1 by Protein Kinase C

描述（由申请人提供）： 该提案描述了一个为期5年的培训计划，以发展为一个独立的临床医生-科学家。 我已经完成了普通外科的住院医师培训，其中包括2年NIH资助的分子心血管生物学研究奖学金。 然后我完成了胸外科的住院医师项目，现在是辛辛那提大学心胸外科的助理教授。 这个项目将建立在我在心脏病G蛋白偶联受体信号传导方面的科学基础之上。 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，并且在培训年轻研究人员方面有着出色的记录。 为了加强训练，Stephen B. Liggett博士将担任共同导师，是心脏β-肾上腺素能受体（β AR）信号传导方面的专家。 此外，一个由备受尊敬的调查人员组成的咨询委员会将提供科学和职业建议。 从代偿性或适应性心肌肥大向心力衰竭转变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，这些信号通路对心肌肥大的发展（Gq偶联受体信号传导）和心脏功能的调节（β AR信号传导）至关重要。 β AR激酶（betaARK 1）是心脏中最丰富的G蛋白偶联受体激酶，在β AR信号传导和心脏功能的调节中至关重要。 蛋白激酶C（PKC）在Gq偶联受体刺激后肥大的发展中被激活，已显示在体外磷酸化并激活β ARK 1。 这一提议将直接检验中心假设，即在体内心肌PKC活性和β ARK 1水平上发生的β AR信号之间存在串扰。 PKC对β ARK 1作用的结果导致β AR信号转导和与心室肥大相关的心功能受损。 基于知识和科学环境，我的部门的承诺，以及我的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生科学家成为成功的独立研究者提供了理想的环境。

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.