Myocardial Regulation of betaARK1 by Protein Kinase C

描述(由申请人提供)： 这份提案描述了一项为期5年的培训计划，以培养成为一名独立的临床医生-科学家。我已经完成了普通外科住院医师培训，其中包括一项由美国国立卫生研究院资助的两年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计划，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中G蛋白偶联受体信号传递方面的科学基础上。阿诺德·施瓦茨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，在培训年轻研究人员方面有着出色的记录。为了加强培训，医学博士Stephen B.Liggett将担任共同导师，他是心脏β-肾上腺素能受体(BetaAR)信号方面的专家。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厚向心力衰竭转变的分子机制尚不清楚。这项研究计划集中于定义心脏内信号通路之间的串扰，这些信号通路对心肌肥厚的发展(GQ偶联受体信号)和心功能的调节(βAR信号)至关重要。β-ARK1是心脏中含量最丰富的G蛋白偶联受体，在β-AR信号转导和心功能调节中起重要作用。蛋白激酶C(PKC)在GQ偶联受体的刺激下被激活，在肥大的发展过程中被激活，在体外被证明是磷酸化和激活βARK1。这一建议将直接检验中心假说，即在活体内，心肌PKC活性与β-ARK1水平上的β-AR信号之间存在串扰。PKC对β-ARK1的作用导致β-AR信号转导和心功能受损，与心肌肥厚相关。 基于学术和科学环境，我的部门的承诺，以及我的导师和顾问委员会的支持，我相信辛辛那提大学心血管研究中心为培养内科科学家成为成功的独立研究人员提供了理想的环境。

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.