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

描述（由申请人提供）： 本提案描述了一个为期5年的培训计划，在分子心脏电病理生理学的学术生涯的发展。主要研究者是一名病理学家，具有心脏电生理学和心肺病理学方面的专业知识，通过该计划，他将扩大他的科学和调查技能。罗切斯特大学医学中心心血管研究所将为主要研究者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，并在顾问Jose Jalife博士和Robert Dirksen博士的额外支持下，研究心律失常的分子机制。 该提案的重点是p90核糖体S6激酶（p90 RSK）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。基于初步数据，实验假设是pQORSK的激活通过Kv4.3的磷酸化降低Ito，f通道活性，抑制心脏复极化，并易导致心脏疾病中的节律障碍。为研究p90 RSK对It 0，f的调节在心律失常中的作用，提出了三个具体目标：1）确定p90 RSK调节It 0，f的分子机制。2)确定p90 RSK激活延长动作电位持续时间的分子机制，并通过抑制lto，f通道活性使其易于心律失常。3)确定干扰p90 RSK信号传导是否通过预防心肌缺血/再灌注和心肌梗死而降低由心肌缺血/再灌注和心肌梗死诱导的节律障碍的频率 下调LTO、F通道活性。不规则的心脏节律是心脏病患者发病和死亡的常见原因。本研究将研究蛋白质p90核糖体S6激酶对心脏节律的影响。这些研究的结果将增强我们对这些异常的分子基础的了解，并可能导致开发新的治疗和/或预防方法。 (End摘要）

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)