RhoE-mediated Sterile Inflammation Regulation in Acute Myocardial Infarction.

RhoE 介导的急性心肌梗塞无菌炎症调节。

基本信息

批准号：
10197204
负责人：
Jiang Chang
金额：
$ 37.13万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197204
关键词：
Acute myocardial infarction American American Heart Association Angioplasty Animal Genetics Animal Model Animals Attenuated Binding Cardiac Cardiovascular Diseases Cell Culture Techniques Clinical Complex Data Down-Regulation Exhibits Foundations Future Gap Junctions Genes Genetic Heart Heart failure Human In Vitro Infarction Infiltration Inflammasome Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Knock-out Lead Link Mass Spectrum Analysis Mediating Modernization Molecular Monomeric GTP-Binding Proteins Mus Mutant Strains Mice Myocardial Infarction Nuclear Import Patients Pharmacology Phenotype Play Post-Translational Regulation Process Prognosis Protein Analysis Proteins Proteomics Recovery Recurrence Regulation Reporting RhoE protein Role Series Signal Transduction Sterility TNF gene TNFRSF5 gene TRIM Motif Testing Therapeutic Time Tissues Transgenic Mice Translations Ubiquitination base cohort cytokine experimental study gain of function genetic manipulation healing heart function improved in vivo injury recovery innovation insight macrophage member mutant neutrophil novel overexpression p65 percutaneous coronary intervention prevent protein complex protein degradation protein protein interaction receptor recruit rho sensor ubiquitin-protein ligase wound healing

项目摘要

PROJECT DESCRIPTION/ABSTRACT Based on the 2016 American Heart Association report, there are about 550,000 Americans newly suffering from myocardial infarction (MI) (defined as first hospitalized MI) and 200,000 recurrent cases. Approximately, one American will have an MI every 42 seconds. While many factors contribute to the prognosis of MI patients, two major determinants are the initial infarction size and the efficiency of the post-MI recovery process. Clinically, modern percutaneous coronary intervention (PCI), known as angioplasty, significantly decreases the extent of the infarction. However, the subsequent wound healing processes, which are initiated and driven by dynamic sterile inflammation, are complicated and elusive. A better understanding of sterile inflammation molecular regulation during acute MI is highly significant, and lays the foundation for all stages of post-MI therapeutics. In this proposal, we have developed a cardiac-specific RhoE (a small G protein, also called Rnd3) deficient- mouse line that is susceptible to MI. RhoE haploinsufficient mice exhibit an intense inflammatory response with compromised cardiac function after MI. We propose multiple systemic approaches including in vitro analysis of protein-protein interactions, cell culture experiments, and in vivo genetic animal assessments with loss- and gain-of-function strategies to investigate the relationship between the expression levels of RhoE and the regulation of post-MI inflammation. The detailed molecular mechanism of RhoE-mediated sterile inflammation regulation will be elucidated. For the first time, RhoE is linked to inflammation regulation. We suggest that RhoE is a new “fine-tuning” factor situated at the nexus of the inflammatory response, and is responsible for balanced sterile inflammation after acute MI. The animal models include heart specific conditional RhoE-deficient mice as well as heart specific RhoE- overexpression transgenic mice. The mechanistic findings from this proposal should result in clinical implications given the fact of significant downregulations of RhoE in heart failure patients. The discovery will provide a foundation for future pharmacological translation.

项目描述/摘要根据 2016 年美国心脏协会报告，大约有 55 万美国人新患心脏病心肌梗塞 (MI)（定义为首次住院 MI）和大约 200,000 例复发病例。每 42 秒就有一名美国人发生心肌梗死虽然影响心肌梗死患者预后的因素有很多，两个主要决定因素是初始梗塞范围和心肌梗死后恢复过程的效率。临床上，现代经皮冠状动脉介入治疗 (PCI)（称为血管成形术）可显着降低然而，梗塞的程度，随后的伤口愈合过程，这是启动和驱动的。动态无菌性炎症是复杂且难以捉摸的更好地了解无菌性炎症。急性心肌梗死期间的分子调控非常重要，为心肌梗死后各个阶段奠定基础疗法。在此提案中，我们开发了一种心脏特异性 RhoE（一种小 G 蛋白，也称为 Rnd3）缺陷- 对 MI 敏感的小鼠系，RhoE 单倍体不足的小鼠表现出强烈的炎症反应。 MI 后心脏功能受损。我们提出了多种系统方法，包括蛋白质-蛋白质相互作用的体外分析、细胞培养实验和体内遗传动物评估以及功能丧失和获得策略研究 RhoE 表达水平与 MI 后炎症调节之间的关系。 RhoE介导的无菌性炎症调节的详细分子机制将得到阐明。我们首次将 RhoE 与炎症调节联系起来。位于炎症反应连接点的因子，负责平衡无菌性炎症急性心肌梗死后。动物模型包括心脏特异性条件性 RhoE 缺陷小鼠以及心脏特异性 RhoE- 该提议的机制发现应产生临床意义。鉴于心力衰竭患者 RhoE 显着下调这一事实，这一发现将提供一个新的思路。为未来的药理学翻译奠定基础。