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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：
10192786
负责人：
Brandon J Biesiadecki
金额：
$ 39万
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/10192786
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.

项目摘要在美国，心力衰竭约占每7例死亡中的1例。心力衰竭导致抑郁心脏收缩期收缩和舒张期舒张减慢，这两者都限制了心脏功能，疾病目前还没有专门增加心肌舒张和改善心肌功能的治疗方法。心脏衰竭心肌舒张由丝氨酸/苏氨酸磷酸化介导。我们已经证明在心脏中鉴定的第一个酪氨酸（Try）磷酸化直接调节心肌功能。我们数据表明，活心肌中Tyr激酶的特异性活化增加了心肌细胞上Tyr的磷酸化。调节蛋白肌钙蛋白I（TnI）。我们进一步证明了增加的TnI Tyr磷酸化有益地改变了啮齿动物和人类心肌收缩特性是加速心肌舒张的关键。这些研究结果支持在衰竭心脏中增加TnI Tyr磷酸化作为改善心肌梗死的潜在新靶点。舒张功能障碍在这项提案中，我们将采用新的遗传和药理学方法，技术来确定有益的加速松弛作用的肌钙蛋白酪氨酸磷酸化作为一种机制改善正常和衰竭心脏的体内舒张功能，并改善心力衰竭患者的存活率。此外，本发明还提供了一种方法，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的舒张作用来靶向治疗人类心力衰竭在非衰竭和衰竭的活的人类心肌中的磷酸化。该提案的具体成果是，确定TnI Tyr磷酸化对衰竭心脏的体内心脏功能的有益作用，将这些功能性作用转化到人心肌中，以建立TnI Tyr磷酸化作为靶点用于未来心力衰竭治疗的发展。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Myofilament Calcium Sensitivity: Mechanistic Insight into TnI Ser-23/24 and Ser-150 Phosphorylation Integration.

DOI：
10.3389/fphys.2016.00567
发表时间：
2016
期刊：
Frontiers in physiology
影响因子：
4
作者：
Salhi HE;Hassel NC;Siddiqui JK;Brundage EA;Ziolo MT;Janssen PM;Davis JP;Biesiadecki BJ
通讯作者：
Biesiadecki BJ

Nucleotide and protein sequences for dog masticatory tropomyosin identify a novel Tpm4 gene product.