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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.

项目总结