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）：心脏收缩功能障碍引起的心脏病是当今美国人群的第一杀手。调节心脏收缩的蛋白质受激酶磷酸化和磷酸酶去磷酸化的紧密翻译后修饰（PTM）调节。心肌收缩调节的中心是肌钙蛋白（TN）蛋白质复合物。为了响应心脏应激，TN复合物受到了许多PTM。磷酸化代表了肌肉PTM的主要机制，其紧密平衡对于正常的心脏功能至关重要。还会发生其他非磷酸化TN PTM。迄今为止，大多数TN蛋白PTM已被研究为孤立事件，但是无法从隔离事件的功能中确定多个TN PTM的合并功能。该提案研究了原发性肌钙蛋白收缩调节磷酸化和其他新型PTM事件，作为合并事件，以更好地了解TN PTM的生理调节功能，因为它们在心脏中发生。为此，我们将采用模型的肌钙蛋白蛋白和包含单个或多个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有更生理的理解，以鉴定新的药物靶标以治疗心脏功能障碍。