Thrombospondin 4 regulates adaptive ER stress response

描述（由申请人提供）：与神经元一样，心肌细胞似乎随着衰老和在疾病状态如心力衰竭期间对蛋白质聚集特别敏感。未折叠的蛋白质反应和内质网（ER）应激途径似乎是唯一的调节心脏，可能是因为这种细胞类型如何处理生产的大型肌节蛋白和生产和不断重塑的精心制作的细胞外基质（ECM），许多大的细胞外蛋白的合成。在该奖项的过去资助周期中，我们确定了血小板反应蛋白（由5个基因（Thbs 1 -5）组成的家族，是钙结合基质细胞蛋白），作为心脏ER应激反应的关键调节因子。在这里，我们提出的假设，血小板反应蛋白是一个适应性ER应激反应，保护心脏免受损伤或蛋白质聚集为基础的疾病的细胞内调节因子。我们进一步假设，血小板反应蛋白3/4基因是专门的心脏保护，而血小板反应蛋白1/2有适应和适应不良的功能域。为了解决这些假设，我们提出了两个具体目标。目的#1将检查心脏中所有5个血小板反应蛋白基因的功能，通过转基因过度表达每个基因，以及在基因靶向小鼠中删除多个家族成员。目的#2将检查血小板反应蛋白提供保护的细胞内机制，这是由于ATF 6a活性或与大ECM蛋白和其他分泌蛋白相关的更一般的伴侣蛋白活性。这些目标应该有助于建立的总体范式;作为ER隔室和高尔基体中的囊泡内调节因子的血小板反应蛋白的关键或原始功能，将是完全新颖的，因此是创新的。研究结果还将为治疗某些类型的心脏病提供新的分子靶点。

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.