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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年美国心脏协会的报告，大约有55万美国人新患心肌梗死（MI）（定义为首次住院MI）和20万例复发病例。大约，每42秒就有一个美国人发生心肌梗死虽然许多因素影响MI患者的预后，两个主要的决定因素是初始梗塞大小和MI后恢复过程的效率。临床上，现代经皮冠状动脉介入治疗（PCI），即血管成形术，梗塞的范围然而，随后的伤口愈合过程，这是启动和驱动，由动态的无菌炎症引起的，是复杂而难以捉摸的。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，并为心肌梗死后的所有阶段奠定了基础治疗学在这项提案中，我们开发了一种心脏特异性RhoE（一种小G蛋白，也称为Rnd 3）缺陷型- 对MI敏感的小鼠品系。RhoE单倍体不足小鼠表现出强烈的炎症反应，心肌梗死后心脏功能受损。我们提出了多种系统的方法，包括体外分析蛋白质-蛋白质相互作用，细胞培养实验，以及采用功能丧失和获得策略的体内遗传动物评估，探讨RhoE表达水平与心肌梗死后炎症反应的关系。详细的分子机制RhoE介导的无菌炎症调节将被阐明。 RhoE首次与炎症调节有关。我们认为RhoE是一种新的“微调” 一种位于炎症反应联系处的因子，负责平衡无菌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-缺陷小鼠。过表达转基因小鼠。从这一建议的机制研究结果应导致临床意义考虑到心力衰竭患者中RhoE显著下调的事实。这一发现将提供一个为今后的药理学翻译奠定基础。