Integrated crosstalk of thin filament post-translational modifications

细丝翻译后修饰的综合串扰

基本信息

批准号：
8504053
负责人：
Brandon J Biesiadecki
金额：
$ 36.55万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8504053
关键词：
Address Animal Model Animals Binding Biochemical Cardiac Cardiac Muscle Contraction Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Complex Development Disease Drug Targeting Echocardiography Equilibrium Event Exhibits Functional disorder Goals Heart Heart Diseases Individual Ischemia Knowledge Microfilaments Modeling Molecular Muscle Myocardial Myocardial Contraction Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Point Mutation Post-Translational Protein Processing Production Property Protein Biochemistry Proteins Public Health Regulation Role Stress Testing Therapeutic Thin Filament Time Transgenic Animals Transgenic Mice Transgenic Organisms Troponin Troponin I Troponin T base drug development genetic regulatory protein heart function hemodynamics improved nitration novel protein complex public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): Heart disease resulting from cardiac contractile dysfunction is the number one killer of people in the US today. The proteins that regulate cardiac contractile are under the tight post-translational modification (PTM) regulation of kinase phosphorylation and phosphatase de-phosphorylation. Central to the regulation of cardiac muscle contraction is the troponin (Tn) protein complex. In response to cardiac stress the Tn complex is subjected to a number of PTMs. Phosphorylation represents the primary mechanism of muscle PTM and it's tight balance is critical to normal heart function. Other non-phosphorylation Tn PTMs also occur. To date most Tn protein PTMs have been studied as isolated events, however the combined function of multiple Tn PTMs cannot be determined from function of the isolated events. This proposal investigates the primary troponin contractile regulation phosphorylation and other novel PTM events as combined events to better understand the physiological regulatory function of Tn PTMs as they occur in the heart. To this end, we will employ model troponin proteins and transgenic animal models containing single or multiple PTMs to evaluate biochemical and animal level function. The goal of these studies is to develop a more physiological understanding of the events that regulate heart function in order to identify novel drug targets to treat cardiac dysfunction.

描述（由申请人提供）：由心脏收缩功能障碍引起的心脏病是当今美国人的头号杀手。调节心脏收缩的蛋白质受到激酶磷酸化和磷酸酶去磷酸化的严格翻译后修饰 (PTM) 调节。调节心肌收缩的核心是肌钙蛋白 (Tn) 蛋白复合物。为了响应心脏应激，Tn 复合物会受到多种 PTM 的影响。磷酸化是肌肉 PTM 的主要机制，其紧密平衡对于正常心脏功能至关重要。还出现其他非磷酸化 Tn PTM。迄今为止，大多数 Tn 蛋白 PTM 已作为孤立事件进行研究，但无法根据孤立事件的功能确定多个 Tn PTM 的组合功能。该提案将初级肌钙蛋白收缩调节磷酸化和其他新的 PTM 事件作为组合事件进行研究，以更好地了解 Tn PTM 在心脏中发生时的生理调节功能。为此，我们将采用模型肌钙蛋白和含有单个或多个 PTM 的转基因动物模型来评估生化和动物水平功能。这些研究的目的是对调节心脏功能的事件产生更生理性的理解，以便确定治疗心脏功能障碍的新药物靶点。