Thrombospondin1-regulated atrophy in the heart

血小板反应蛋白1调节的心脏萎缩

基本信息

批准号：
10578361
负责人：
Jeffery D Molkentin
金额：
$ 60.36万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10578361
关键词：
Acute Adult Affect Anorexia Atrophic Automobile Driving Autophagocytosis Autophagosome Bed rest Binding Biological Biological Assay Biological Process Biotin Blood Platelets Calcium Binding Caloric Restriction Cardiac Cardiac Myocytes Cardiomyopathies Catabolic Process Catabolism Cells Cellular biology Complex Data Disease Doxorubicin Dystrophin EIF-2alpha Endoplasmic Reticulum Equilibrium Extracellular Matrix Extracellular Matrix Proteins Family Family member Gene Expression Profile Gene Family Gene Targeting Gene Transfer Genes Genetic Transcription Glycoproteins Heart Heart Diseases Heart Hypertrophy Heart Injuries Heart failure Immunohistochemistry Immunoprecipitation Injury Integrins Investigation Knockout Mice LAMP-2 Ligase Location Lysosomes Malnutrition Mammals Mediating Medical Membrane Messenger RNA Metabolic Molecular Molecular Chaperones Movement Mus Mutant Strains Mice Myocardium Neonatal Nodal Nutrient Paper Pathologic Pathway interactions Patients Physiological Play Process Protein Glycosylation Protein Secretion Proteins Regulation Regulatory Pathway Role Sarcolemma Secretory Vesicles Series Signal Pathway Signal Transduction Skeletal Muscle Stains Starvation Stimulus Stress Striated Muscles Testing Thrombospondin 1 Thrombospondins Time Tissues Transgenic Mice Ventricular Remodeling Vesicle Work Workload adenoviral mediated biological adaptation to stress cancer cachexia endoplasmic reticulum stress healing in vivo innovation mortality mouse model neonatal mice novel overexpression pressure response skeletal muscle wasting transcription factor

项目摘要

Abstract Like skeletal muscle myofibers, cardiomyocytes in the heart constantly adjust their size based on perceived workload or disease stimulation, in which hypertrophic versus atrophic pathways are in balance to achieve an appropriate equilibrium matched to real-time workloads. In a less appreciated process, both heart and skeletal muscle can reduce size through molecular regulatory pathways that cause tissue catabolism. This reduction in size is referred to as atrophy and this process can underlie tissue remodeling and responses to disease stimulation or loss of sufficient nutrients (such as starvation) in which both tissues can serve as metabolic reservoirs. Here we uncovered a novel function for thrombospondin1 as a regulator of both cardiac and skeletal muscle atrophy. We have previously shown that the thrombospondin gene family (Thbs1- 5) plays a critical role in membrane stability through effects on the ER stress response and secretory pathways, as well as controlling the integrin and dystrophin-glycoprotein complexes present with the sarcolemma. However, more recently we have discovered that Thbs1 is uniquely induced by disease stimuli associated with cardiac remodeling and caloric restriction, and that Thbs1 uniquely regulates cellular atrophy and autophagy through an intracellular pathway within the ER/SR that functions at 2 levels. 1) Thbs1 directly binds and regulates the ER stress factor PERK and eIF2α to mediate cardiomyocyte atrophy through the transcription factor ATF4, and 2) Thbs1 selectively expands lysosomes and the vesicular pathway of autophagy. Hence, we hypothesize that Thbs1 is an ER-dependent chaperone that mediates cardiomyocyte size reduction, in part, by driving the catabolic process through autophagy. To investigate this hypothesis, we will interrogate 2 specific aims: 1) To examine the mechanisms of cardiac atrophy and autophagy through PERK/eIF2α/ATF4 signaling mediated by Thbs1 within the ER compartment. 2) To examine a mechanism whereby cardiac autophagy is mediated by Thbs1- dependent formation of lysosomes and associated catabolic vesicular activity. The proposed course of investigation will be conducted in both cultured cardiomyocytes and in genetically modified mouse models so that both reductionist and mechanistic approaches can be taken, as well as in vivo assessment in a physiologically relevant context. The proposed application is innovative as it will define for the first time what appears to be a novel cell biology pathway through Thbs1 that controls striated muscle remodeling through atrophy and autophagy.

抽象的与骨骼肌肌纤维一样，心脏中的心肌细胞会根据情况不断调整其大小。感知到的工作量或疾病刺激，其中肥大与萎缩的途径处于平衡以达到与实时工作负载相匹配的适当平衡。在赞赏的过程中，心脏和骨骼肌都可以通过分子缩小尺寸引起组织分解代谢的调节途径被称为萎缩。这个过程可能是组织重塑和对疾病刺激或丧失的反应的基础足够的营养（例如饥饿），两个组织都可以作为代谢库。在这里，我们发现了血小板反应蛋白1作为心脏和心脏功能调节剂的新功能。我们之前已经证明血小板反应蛋白基因家族（Thbs1-）。 5) 通过影响内质网应激反应在膜稳定性中发挥关键作用分泌途径，以及控制整合素和肌营养不良蛋白-糖蛋白复合物然而，最近我们发现 Thbs1 是独特的。由与心脏重塑和热量限制相关的疾病刺激引起，并且 Thbs1 通过细胞内途径独特地调节细胞萎缩和自噬 ER/SR 在 2 个水平上发挥作用 1) Thbs1 直接结合并调节 ER 应激因子。 PERK 和 eIF2α 通过转录因子 ATF4 介导心肌细胞萎缩，2) Thbs1 选择性地扩展溶酶体和自噬的囊泡途径。 Thbs1 是一种 ER 依赖性伴侣，介导心肌细胞大小部分通过自噬驱动分解代谢过程来减少。假设，我们将询问 2 个具体目标：1）检查心脏萎缩的机制以及通过 ER 内 Thbs1 介导的 PERK/eIF2α/ATF4 信号传导进行自噬 2) 研究Thbs1-介导的心脏自噬机制。溶酶体的依赖性形成和相关的分解代谢囊泡活性。研究过程将在培养的心肌细胞和遗传细胞中进行改良的小鼠模型可以采用还原论和机械论方法，如以及生理相关背景下的体内评估。创新，因为它将首次定义一种新的细胞生物学途径 Thbs1 通过萎缩和自噬控制横纹肌重塑。