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：
9448622
负责人：
Brandon J Biesiadecki
金额：
$ 38.98万
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 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9448622
关键词：
Adult Americas Animal Disease Models Calcium Cardiac Cardiac health Cell physiology Cells Cessation of life Cyclic AMP-Dependent Protein Kinases Data Depressed mood Development Disease Disease Progression Echocardiography Fibrosis Functional disorder Funding Future Genetic Heart Heart failure Histology Human Impairment Knock-in Mouse Measures Mediating Microfilaments Morphology Mus Muscle Cells Muscle function Myocardial Myocardial Ischemia Myocardium Outcome Peptides Pharmacology Phosphorylation Phosphotransferases Physiological Post-Translational Protein Processing Property Protein Tyrosine Kinase Proteomics Relaxation Rodent Role Serine Serine/Threonine Phosphorylation Signal Transduction Techniques Testing Thin Filament Threonine Translating Troponin I Tyrosine Tyrosine Phosphorylation genetic regulatory protein heart function improved improved functioning in vivo inhibitor/antagonist novel pressure protein expression targeted treatment therapeutic target therapy development

项目摘要

PROJECT SUMMARY Heart failure accounts for approximately 1 out of every 7 deaths in America. Heart failure results in depressed cardiac systolic contraction and slowed diastolic relaxation, both of which limit heart function and contribute to disease. Currently there is no therapy to specifically increase myocardial relaxation and improve function of the failing heart. Myocardial relaxation is mediated by serine/threonine phosphorylation. We have demonstrated the first tyrosine (Try) phosphorylation identified in the heart directly modulates cardiac muscle function. Our data demonstrates specific activation of Tyr kinases in living myocardium increase Tyr phosphorylation on the regulatory protein troponin I (TnI). We further demonstrate increased TnI Tyr phosphorylation beneficially alters rodent and human cardiac muscle contractile properties key to accelerating myocardial relaxation. These findings support increasing TnI Tyr phosphorylation in the failing heart as a potential novel target to improve diastolic dysfunction in heart failure. In this proposal we will employ novel genetic and pharmacological techniques to define the beneficial accelerated relaxation effects of TnI Tyr phosphorylation as a mechanism improve in vivo diastolic function of the normal and failing heart and improve survival in heart failure. In addition, we will begin to translate these beneficial effects of TnI Tyr phosphorylation towards the future development of a targeted therapy for human heart failure by establishing the relaxation effects of increasing TnI Tyr phosphorylation in non-failing and failing living human myocardium. The specific outcome of this proposal is to establish the beneficial effects of TnI Tyr phosphorylation on in vivo heart function of the failing heart and to translate these functional effects into the human myocardium to establish TnI Tyr phosphorylation as a target for future heart failure therapy development.

项目摘要心力衰竭约占美国每7人死亡中的1个。心力衰竭导致沮丧心脏收缩收缩和舒张压放松减慢，这两者都限制了心脏功能并有助于疾病。目前尚无疗法来特别增加心肌放松并提高功能心脏失败。心肌松弛是由丝氨酸/苏氨酸磷酸化介导的。我们已经证明了心脏中鉴定出的第一个酪氨酸（尝试）磷酸化直接调节心肌功能。我们的数据表明，在活心肌中，特有激酶在生命心肌中的特异性激活增加了Tyr磷酸化调节性蛋白质肌钙蛋白I（TNI）。我们进一步证明TNI Tyr磷酸化有益地改变啮齿动物和人类心脏肌肉收缩特性是加速心肌松弛的关键。这些研究结果支持在失败的心脏中增加TNI Tyr磷酸化，这是一个潜在的新型目标，以改善心力衰竭的舒张功能障碍。在此提案中，我们将采用新颖的遗传和药理学定义TNI Tyr磷酸化作为一种机制的有益加速放松效应的技术改善正常和心脏衰竭的体内舒张功能，并改善心力衰竭的存活率。此外，我们将开始将Tni Tyr磷酸化的这些有益作用转化为未来的发展通过建立增加TNI Tyr的放松效果的针对人类心力衰竭的靶向疗法非失败和失败的人类心肌的磷酸化。该提议的具体结果是建立TNI Tyr磷酸化对失败心脏的体内心脏功能的有益作用将这些功能效应转化为人体心肌，以建立TNI Tyr磷酸化作为靶标用于未来的心力衰竭疗法开发。