Role of Modulation of Ito,f by Kinases in Cardiac Dysrhythmias

描述(由申请人提供)： 本提案描述了一项为期5年的培训计划，旨在发展分子心脏电病理生理学的学术生涯。首席研究员是一位在心脏电生理学和心肺病理学方面具有专业知识的病理学家，通过这个项目，他将扩展他的科学和调查技能。罗彻斯特大学医学中心心血管研究所将为首席研究员提供一个理想的环境，在经验丰富的导师Jun-lchi Abe博士和委员会成员Bradford Berk博士和Mark Taubman博士的专家指导下，以及Jose Jalife博士和Robert Dirksen顾问的额外支持下，研究涉及心律失常的分子机制。该提案的重点是p90核糖体S6激酶(P90RSK)在心律失常中的作用，心律失常是不同类型心脏病发病率和死亡率的主要原因。根据初步数据，实验假设pQORSK的激活通过Kv4.3的磷酸化降低LTO，f通道的活性，延长心脏复极，并易导致心脏病的心律失常。为了研究p90RSK对It0.f的调控在心律失常中的作用，我们提出了三个具体的目标：1)确定p90RSK调控LTO，f的分子机制。2)研究p90RSK激活通过抑制LTO，f通道活性，延长动作电位时程，诱发心律失常的分子机制。3)研究扰动p90RSK信号通路是否通过抑制LTO、f通道活性而减少心肌缺血/再灌流和心肌梗死所致心律失常的发生。心律不齐是心脏病患者发病率和死亡率的常见原因，本研究将探讨P90核糖体S6蛋白对心律的影响。这些研究的结果将加强我们对这些异常的分子基础的了解，并可能导致开发治疗和/或预防这些异常的新疗法。 (摘要结束)

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in molecular cardiac electropathophysiology. The principal investigator is a pathologist with an expertise in cardiac electrophysiology and cardiopulmonary pathology, and through this program he will expand upon his scientific and investigative skills. The Cardiovascular Research Institute of the University of Rochester Medical Center will provide the principal investigator with an ideal setting for studying the molecular mechanisms involved in cardiac dysrhythmias under the expert guidance of experienced mentor Dr. Jun-lchi Abe and committee members Drs. Bradford Berk and Mark Taubman, and with additional support from consultants Drs. Jose Jalife and Robert Dirksen. The proposal focuses on the role of the p90 Ribosomal S6 Kinase (p90RSK) in cardiac dysrhythmias, which are a leading cause of morbidity and mortality in different types of heart disease. Based on the preliminary data, the experimental hypothesis is that activation of pQORSK reduces lto,f channel activity via phosphorylation of Kv4.3, prolongs cardiac repolarization, and predisposes to dysrhythmias in cardiac disease. To investigate the role of modulation of It0.f by p90RSK in cardiac dysrhythmias three specific aims are proposed: 1) Determine the molecular mechanism by which lto,f is modulated by p90RSK. 2) Determine the molecular mechanism by which activation of p90RSK prolongs action potential duration and predisposes to dysrhythmias via inhibition of lto,f channel activity. 3) Determine if perturbing p90RSK signaling reduces frequency of dysrhythmias induced by cardiac ischemia/reperfusion and myocardial infarction via preventing downregulation of lto,f channel activity. Irregular heart rhythms are a common cause of morbidity and mortality in patients with heart disease This research will investigate the effects of the protein p90 Ribosomal S6 Kinase on heart rhythms. The results of these studies will enhance our knowledge of the molecular basis of these abnormalities and could lead to development of new therapies for their treatment and/or prevention. (End of Abstract)