Post-translational Modification in Cardiac Muscle

心肌翻译后修饰

• 批准号: 8115759
• 负责人: Brandon J Biesiadecki
• 金额: $ 24.9万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115759
• 关键词: Affect; Affinity; Binding; Ca(2+)-Transporting ATPase; Calcium; Cardiac; Cardiac Myocytes; Cardiomyopathies; Data; Development; Disease; Fiber; Functional disorder; Goals; Heart Diseases; Heart failure; Human; Modification; Molecular; Myocardial Infarction; Myocardium; Phosphorylation; Post-Translational Protein Processing; Protein Binding; Proteins; Reperfusion Therapy; Role; Signal Transduction; Stress; Thin Filament; Transgenic Mice; Tropomyosin; base; heart function; improved; insight; mortality; nitration; novel; overexpression; reconstitution; therapy development

Tropomyosin (Tm) is modified by both posphorylation and nitration post-translational modifications. To date tiie functional significance of Tm pfiospliorylation and nitration are not well understood. It is the goal of this proposal to identify the effect of Tm phosphorylation and nitration on its interactions with the sarcomeric proteins and on activation of the sarcomeric thin filament. Recent data has suggested the post-transiational modification of Tm may be regulated, therefore we further propose to investigate the effect of cardiac stress on the level of Tm post-translational modifications as a novel signaling mechanism to alter cardiac sarcomeric contraction. This application contains three specific aims to investigate these questions. 1) Does cardiac stress alter the post-tranlational modification of Tm to affect contractile function? 2) Does the posttranslational modification of Tm by phsophorylation or nitration alter its interactions within the thin filament protein network? 3) Do post-transiational modifications of Tm alter Ca2+ activation of the thin filament? These aims wiil be carried out by investigating the effect of Tm that has been modified by either phosphorylation or nitration on Tm binding affinity to the other sarcomeric thin filament proteins, the binding of Ca2+ and the ATPase activity of reconstituted thin filaments. We also propose to investigate the effect of cardiac stress on Tm post-translational modifications by treating cardiac myocytes with ischemic reperfusion followed by identification of Tm phosphorylation and nitration levels. We will investigate the significance of Tm phosphorylation by investigating calcium regulated force development in cardiac fibers from transgenic mice overexpressing pseudo-phosphorylated Tm. These studies will provide a much needed molecular understanding of how the post-translaitonal modification of Tm functions to affect cardiac contraction at the sarcomeric level and its role as a novel signaling mechanism to affect cardiac contraction in ischemic reperfusion. The findings from these studies are direclty relevant to understanding the molecular basis of cardiac dysfunction in human myocardial infarction. These studies wiil also provide new insight into potential pharmacotheriputic treatments to improve heart function in both myocardial infarction and disease.

原肌球蛋白(TM)通过磷酸化后修饰和翻译后硝化修饰来修饰。到目前为止，TM的功能意义还不是很清楚。这项建议的目的是确定TM的磷酸化和硝化对其与肌瘤蛋白的相互作用和对肌瘤细丝激活的影响。最近的数据表明TM的转换后修饰可能是受调控的，因此我们进一步建议研究心脏应激对TM翻译后修饰水平的影响，作为改变心肌肌节收缩的新的信号机制。本应用程序包含调查这些问题的三个具体目标。1)心脏应激是否改变TM的翻译后修饰以影响收缩功能？2)TM的磷酸化或硝化翻译后修饰是否改变其在细丝蛋白网络中的相互作用？3)TM的翻译后修饰是否改变细丝的钙激活？ 这些目标将通过调查TM的影响来实现，TM已被任何一方修改 磷酸化或硝化对TM与其他肌节细丝蛋白的结合亲和力、钙离子的结合以及重组细丝的ATPase活性的影响。我们还建议通过处理缺血再灌注的心肌细胞，然后鉴定TM的磷酸化和硝化水平，来研究心脏应激对TM翻译后修饰的影响。我们将通过研究过度表达假磷酸化TM的转基因小鼠心肌纤维中钙调控力的发展来研究TM磷酸化的意义。这些研究将提供一个急需的分子理解，即TM的跨膜后修饰如何在肌节水平影响心脏收缩，以及它作为一种新的信号机制在缺血再灌流中影响心脏收缩的作用。这些研究的结果直接关系到了解人类心肌梗死心功能不全的分子基础。这些研究还将为改善心肌梗死和疾病的心功能的潜在药物治疗提供新的见解。

项目成果

Advanced glycation end product cross-link breaker attenuates diabetes-induced cardiac dysfunction by improving sarcoplasmic reticulum calcium handling.

• DOI: 10.3389/fphys.2012.00292
• 发表时间: 2012
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Kranstuber AL;Del Rio C;Biesiadecki BJ;Hamlin RL;Ottobre J;Gyorke S;Lacombe VA
• 通讯作者: Lacombe VA