Thrombospondin 4 regulates adaptive ER stress response

血小板反应蛋白 4 调节适应性 ER 应激反应

基本信息

批准号：
8965510
负责人：
Jeffery D Molkentin
金额：
$ 48.44万
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：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8965510
关键词：
Accounting Address Aging Award Binding Calcium Calcium Binding Calcium-Binding Proteins Cardiac Cardiac Myocytes Cardiomyopathies Cessation of life Coupling Cultured Cells Data Disease Drosophila genus Endoplasmic Reticulum Event Extracellular Matrix Extracellular Matrix Proteins Extracellular Protein Family Family member Fibroblasts Figs - dietary Funding GRP78 gene Gene Targeting Gene Transfer Techniques Genes Golgi Apparatus Health Heart Heart Diseases Heart Injuries Heart failure Injury Knockout Mice Maps Mediating Mediator of activation protein Medical Membrane Membrane Proteins Modeling Molecular Molecular Chaperones Molecular Target Mus Muscle Fibers Muscular Dystrophies Myopathy Neurons Pathway interactions Process Production Protein Biosynthesis Proteins Role Series Signal Transduction Skeletal Muscle Stress Structural Genes Testing Thrombospondins Time Transgenic Mice activating transcription factor base biological adaptation to stress endoplasmic reticulum stress extracellular fly in vivo innovation loss of function mutant novel overexpression pressure protein aggregation protein degradation protein function repaired response secretion process thrombospondin 4 trafficking transcription factor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Like neurons, the cardiac myocyte appears to be especially susceptible to protein aggregation with aging and during disease states such as heart failure. The unfolded protein response and endoplasmic reticulum (ER) stress pathways appear to be uniquely regulated in the heart, possibly because of how this celltype has to deal with production of large sarcomeric proteins and the production and continual remodeling of an elaborate extracellular matrix (ECM), with synthesis of many large extracellular proteins. In the past funding cycle of this award we identified thrombospondins, which comprise a family of 5 genes (Thbs1-5) and are calcium binding matracellular proteins, as critical regulators of the ER stress response in the heart. Here we propose the hypothesis that thrombospondin proteins are intracellular regulators of an adaptive ER stress response that protects the heart from injury or protein aggregation-based disease. We further hypothesize that thrombospondin3/4 genes are exclusively cardioprotective while thrombospondin1/2 have both adaptive and maladaptive functional domains. To address these hypotheses we propose 2 specific aims. Aim #1 will examine the function of all 5 thrombospondin genes in the heart, both by transgenesis to overexpress each, as well as in gene-targeted mice in which multiple family members are deleted. Aim #2 will examine the intracellular mechanisms whereby thrombospondin proteins provide protection as either due to ATF6a activity or a more general chaperone activity associated with large ECM proteins and other secreted proteins. The overall paradigm that these aims should help establish; that being a critical or primordial function for thrombospondins as intra-vesicular regulators in the ER compartment and Golgi, would be completely novel and hence innovative. The results would also suggest new molecular targets for exploitation in treating select forms of heart disease.

描述（由申请人提供）：像神经元一样，心肌细胞似乎特别容易受到衰老和疾病状态（例如心力衰竭）的蛋白质聚集的影响。展开的蛋白质反应和内质网（ER）应力途径似乎在心脏中受到独特的调节，这可能是因为这种细胞类型如何应对大型肉瘤蛋白的产生以及许多大型细胞外素外蛋白的生产以及持续的重塑，并持续重塑了许多大型外细胞外蛋白。在该奖项的过去筹资周期中，我们确定了血小板传播，其中包括一个5个基因（THBS1-5）的家族，是钙结合基质细胞蛋白，是心脏中质期应力反应的关键调节剂。在这里，我们提出了以下假设：血小板蛋白蛋白是适应性ER应激反应的细胞内调节剂，可保护心脏免受损伤或蛋白质聚集的疾病。我们进一步假设血栓形成蛋白3/4基因仅是心脏保护性的，而血小板传播1/2既具有自适应和不良适应功能域。为了解决这些假设，我们提出了2个具体目标。 AIM＃1将通过转基因和针对基因靶向的小鼠进行过表达的转基因来检查所有5种血小板传播基因的功能，其中删除了多个家庭成员。 AIM＃2将检查细胞内机制，通过这些机制，血小板蛋白蛋白可以通过ATF6A活性或与大型ECM蛋白和其他分泌蛋白相关的更一般的伴侣活性提供保护。这些目标应该有助于建立的总体范式；作为血小板蛋白的关键或原始功能是ER隔室和高尔基体中的腔内调节剂，将是完全新颖的，因此是创新的。结果还将表明在治疗精选形式的心脏病中剥削的新分子靶标。