Thrombospondin1-regulated atrophy in the heart

血小板反应蛋白1调节的心脏萎缩

• 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
• 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

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 像骨骼肌肌纤维一样，心脏中的心肌细胞不断根据 感知到的工作量或疾病刺激，其中肥厚型与萎缩途径所在 平衡以实现与实时工作负载相匹配的适当等效的。少 欣赏过程，心脏和骨骼肌都可以通过分子降低大小 引起组织分解代谢的调节途径。这种尺寸的降低称为萎缩 此过程可以是组织重塑的基础，并对疾病刺激或丧失的反应 足够的营养（例如饥饿），其中两种组织都可以用作代谢储层。 在这里，我们发现了血小板传播1作为心脏和心脏的调节剂的新功能 骨骼肌萎缩。我们以前已经表明，血小板传播基因家族（THBS1- 5）通过对ER应力反应的影响和 秘书途径，以及控制整联蛋白和肌营养不良蛋白复合蛋白复合物 存在肌膜。但是，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的，并且 THBS1独特地调节细胞萎缩和自噬通过细胞内途径 在2个级别起作用的ER/SR。 1）THBS1直接结合并调节ER应力因子 PERK和EIF2α通过转录因子ATF4介导心肌细胞萎缩，2） THBS1有选择地扩展溶酶体和自噬的囊泡途径。因此，我们 假设THBS1是ER依赖性的伴侣，可介导心肌细胞大小 部分通过通过自噬来驱动分解代谢过程来减少。调查这一点 假设，我们将询问2个具体目的：1）检查心脏萎缩的机制 通过ER内THBS1介导的PERK/EIF2α/ATF4信号传导自噬 车厢。 2）检查一种机制，通过THBS1-介导心脏自噬。 溶酶体的依赖形成和相关的分解代谢囊泡活性。提议 研究过程将在培养的心肌细胞和遗传学上进行 修改的鼠标模型，以便可以采用还原主义和机械方法，例如 以及在身体相关的情况下的体内评估。拟议的申请是 创新性，因为它将首次定义是一种新颖的细胞生物学途径 通过萎缩和自噬来控制条纹肌肉重塑的THBS1。