Innate Immunity Pathways in Autophagy Signaling in Cardiac Myocytes

心肌细胞自噬信号传导的先天免疫途径

基本信息

批准号：
9492022
负责人：
Abhinav Diwan
金额：
$ 3.68万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9492022
关键词：
Ablation Adult Age Autophagocytosis Biological Models Cardiac Cardiac Myocytes Cardiomyopathies Cause of Death Cell Fractionation Cell Survival Cessation of life Code Coronary Arteriosclerosis Data Development Echocardiography Endoplasmic Reticulum Ensure Excision Fibrosis Heart Heart failure Homeostasis Hypoxia Impairment In Vitro Infarction Injury Ischemia Knockout Mice LoxP-flanked allele Lysosomes Mediating Membrane Methods Mission Mitochondria Mitochondrial Proteins Molecular Mus Myocardial Infarction Myocardial Ischemia Myocardium Natural Immunity Organelles Outer Mitochondrial Membrane PINK1 gene Pathway interactions Perinatal Play Process Protein-Serine-Threonine Kinases Proteins Proteomics Reagent Recruitment Activity Reperfusion Injury Reperfusion Therapy Role Signal Transduction Signaling Protein Stress Structure System TNF Receptor-Associated Factors TRAF2 gene Testing Transgenic Organisms Tumor Necrosis Factor Receptor Ubiquitin United States United States National Institutes of Health cardiogenesis endoplasmic reticulum stress hemodynamics in vivo mitochondrial autophagy mortality mutant novel overexpression prevent protein degradation public health relevance restoration sensor ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Efficient removal of damaged sub-cellular organelles via the autophagy-lysosome machinery is critical for maintaining cardiac myocyte viability in homeostasis and with ischemia-reperfusion (IR) injury. Emerging evidence implicates an essential role for innate immunity proteins as intracellular `damage sensors' to orchestrate their autophagic removal. One such protein, TRAF2 (Tumor necrosis factor Receptor-Associated Factor-2), activates cytoprotective signaling downstream of both TNF receptors to prevent IR-induced cardiomyocyte death. We have recently discovered a novel role for TRAF2 as an E3 ubiquitin ligase in autophagic removal of damaged mitochondria in cardiac myocytes. Mitochondrial damage triggers stabilization of PINK1, a serine-threonine kinase, on the outer mitochondrial membrane, which recruits PARKIN, an E3 ubiquitin ligase to ubiquitin- tag mitochondrial proteins for degradation. Whether PINK1 signaling also recruits TRAF2 to damaged mitochondria; and whether TRAF2, plays a non-redundant role vis-à-vis PARKIN in mitochondrial autophagy, in vivo, is not known. In parallel studies, we have also uncovered evidence for endoplasmic reticulum (ER) permeabilization under conditions of ER stress and in cardiac IR injury. ER damage activates IRE1α, an ER-localized serine-threonine kinase and RNAase, which interacts with TRAF2; and in-vitro studies indicate that IRE1α-TRAF2 signaling at the mitochondria associated membranes (MAM) orchestrates autophagy of damaged mitochondria and ER. In this proposal, we will test the hypothesis that TRAF2 signaling mediates selective autophagy of endoplasmic reticulum and mitochondria to regulate cardiac myocyte survival in homeostasis and under stress; under three specific aims. In aim 1, we will determine the role of TRAF2 in cardiac myocyte survival in homeostasis and under stress. In aim 2, we will examine the role of TRAF2 vis-à-vis PARKIN in mitochondrial autophagy in cardiac myocytes. In aim 3, we will determine the role of IRE1α-TRAF2 signaling axis in ER-phagy in cardiac myocytes. These studies will elucidate the cellular basis for targeting TRAF2 as an innate immunity sensor that coordinates autophagic removal of damaged organelles at the mitochondria-ER interface (MAM) to enhance cardiomyocyte survival in myocardial infarction and prevent heart failure, a key mission of the NIH.

描述（由适用提供）：通过自噬 - 散肌体机械有效去除受损的亚细胞细胞器对于维持心稳态中的心肌细胞生存能力和缺血 - 重新灌注（IR）损伤至关重要。新兴的证据意味着先天免疫学蛋白作为细胞内“损伤传感器”的重要作用，可以协调其自噬去除。一种这样的蛋白质TRAF2（肿瘤坏死因子受体相关因子2），激活两个TNF受体下游的细胞保护信号传导，以防止IR诱导的心肌细胞死亡。最近，我们发现了TRAF2作为E3泛素连接酶在心肌细胞中受损的线粒体受损中的新作用。线粒体损伤触发了丝氨酸 - 硫代激酶Pink1的稳定性，在外部线粒体膜上诱导了Pink1，它募集了Parkin，parkin，parkin，一种E3泛素连接酶以泛素蛋白 - 标记线粒体蛋白质的蛋白质进行脱机。 Pink1信号是否还募集TRAF2损坏线粒体；而且，无论traf2是否在线粒体自噬中扮演帕金（in Vivo）中的帕金（Parkin）扮演非冗余角色，尚不清楚。在平行研究中，我们还发现了在ER应激和心脏IR损伤条件下内质网（ER）通透性的证据。 ER损伤激活了与TRAF2相互作用的ER定位的丝氨酸 - 硫代激酶和RNAase的IRE1α。 Vitro研究表明，线粒体相关膜（MAM）处的IRE1α-Traf2信号传导策划了损坏的线粒体和ER的自噬。在该提案中，我们将检验以下假设：TRAF2信号传导介导内质网和线粒体的选择性自噬以调节体内平衡和压力下的心肌细胞生存。在三个具体目标下。在AIM 1中，我们将确定TRAF2在心肌细胞生存中的作用在体内平衡和压力下。在AIM 2中，我们将研究TRAF2相对于帕金（Parkin）在心肌细胞中线粒体自噬中的作用。在AIM 3中，我们将确定IRE1α-Traf2信号轴在心肌细胞中ER-PHAGY中的作用。这些研究将阐明将TRAF2作为先天免疫学传感器靶向的细胞基础，该传感器可以协调线粒体-ER界面（MAM）处受损细胞器的自噬，以增强心肌梗死中心肌细胞的生存，并防止心力衰竭，预防NIH的关键任务。