Post-translational Modification in Cardiac Muscle

心肌翻译后修饰

• 批准号: 7939634
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939634
• 关键词: Affect; Affinity; Binding; Ca(2+)-Transporting ATPase; Calcium; Cardiac; Cardiac Myocytes; 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.

Tropomyosin（TM）通过phy骨和硝化后的翻译后修饰进行了修饰。迄今为止，TM PfioSplioryLation和硝化的功能意义尚不清楚。该提案的目的是确定TM磷酸化和硝化对其与肉瘤蛋白相互作用的影响以及肌肉薄丝的激活。最近的数据表明，可能会调节TM的传输后修饰，因此我们进一步建议研究心脏应激对TM平移后翻译后修饰水平的影响，这是一种新的信号传导机制，以改变心脏讽刺的收缩。该应用程序包含研究这些问题的三个特定目的。 1）心脏压力是否会改变TM的跨性后修饰以影响收缩功能？ 2）通过phsophorylation或硝化对TM的翻译​​后修饰会改变其在薄丝蛋白网络中的相互作用吗？ 3）TM的传输后修饰是否改变了薄丝的Ca2+激活？ 这些目标是通过研究TM的效果来实现的 TM结合亲和力与其他肌膜细丝蛋白的磷酸化或硝化作用，Ca2+的结合以及重构的薄丝的ATPase活性。我们还建议研究心脏应激对TM翻译后修饰的影响，通过治疗心肌细胞与缺血性再灌注，然后鉴定出TM磷酸化和硝化水平。我们将通过研究过表达伪磷酸化TM的转基因小鼠的心脏纤维中钙调节力的发育来研究TM磷酸化的重要性。这些研究将提供急需的分子理解，以了解TM功能的透射后修饰如何影响肌肉收缩水平的心脏收缩及其作为一种新型信号机制的作用，以影响缺血性再灌注中心脏收缩。这些研究的发现与理解人心肌梗死中心脏功能障碍的分子基础有关。这些研究还提供了对潜在的药物疗法治疗的新见解，以改善心肌梗塞和疾病的心脏功能。