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.

项目概要在美国，每 7 例死亡中就有 1 例死于心力衰竭。心力衰竭导致抑郁心脏收缩期收缩和舒张期舒张减慢，这两者都会限制心脏功能并导致疾病。目前尚无专门增加心肌舒张和改善心肌功能的疗法失败的心。心肌舒张是由丝氨酸/苏氨酸磷酸化介导的。我们已经证明了在心脏中发现的第一个酪氨酸（Try）磷酸化直接调节心肌功能。我们的数据表明活体心肌中 Tyr 激酶的特异性激活会增加心肌上的 Tyr 磷酸化调节蛋白肌钙蛋白 I (TnI)。我们进一步证明 TnI Tyr 磷酸化的增加有益于改变啮齿动物和人类心肌收缩特性是加速心肌舒张的关键。这些研究结果支持增加衰竭心脏中的 TnI Tyr 磷酸化作为改善心脏功能的潜在新目标心力衰竭中的舒张功能障碍。在本提案中，我们将采用新的遗传和药理学方法确定 TnI Tyr 磷酸化的有益加速松弛效应机制的技术改善正常和衰竭心脏的体内舒张功能并提高心力衰竭患者的生存率。此外，我们将开始将 TnI Tyr 磷酸化的这些有益影响转化为未来的发展通过增加 TnI Tyr 的松弛作用来治疗人类心力衰竭非衰竭和衰竭活人心肌中的磷酸化。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影响，并将这些功能效应转化为人类心肌，以 TnI Tyr 磷酸化为目标为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）

Should we treat heart failure with phosphatase inhibitors? Better to start at the end.

DOI：
10.1016/j.yjmcc.2015.10.020
发表时间：
2015-12
期刊：
Journal of molecular and cellular cardiology
影响因子：
5
作者：
Biesiadecki BJ;Ziolo MT
通讯作者：
Ziolo MT

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.