Thrombospondin 4 regulates adaptive ER stress response

摘要 心肌细胞中的ER/SR区段高度专一地控制兴奋时的钙离子流动。 收缩偶联(ECC)，以及调节蛋白质合成和应激反应 蛋白质。传统的内质网应激反应包括感知钙和细胞内未折叠或受损的蛋白质 内质网通过3条不同的通路启动一系列信号来改变蛋白质合成和其他 细胞对应激的适应特征。我们最近发现凝血酶反应蛋白4(TSP4)是一种应激诱导因子 在分泌到细胞外基质(ECM)之前驻留在ER/SR中一段时间的因子， 它会改变内质网的应激反应。心脏表达TSP1、TSP2和TSP4，每一个都是 在受伤或应激刺激后显著上调。有趣的是，TSP4只在心脏中表达 和骨骼肌，它似乎属于与TSP1和TSP2完全不同的功能亚类。我们 已经确定了TSP4的一种新功能，它是一种心脏诱导蛋白，可以显著提高TSP4的含量 而ER/SR的功能导致更大的收缩能力，增加了适应性内质网应激的活性 反应和保护免受心力衰竭诱发的刺激。因此，我们假设TSP4是一部小说 适应性应激反应因子，有利于ER/SR功能，提供心脏保护。在本项目中，我们将： 1)确定TSP4是否通过适应性内质网应激反应通路保护心脏免于衰竭 参与，2)研究介导TSP4依赖性心脏保护的内质网应激反应因子， 3)确定TSP4如何以及在哪里发出适应性内质网应激反应的信号。我们将使用TSP4转基因 和以基因为靶标的小鼠来研究这三个特定的目标，以及许多具有 内质网应激信号改变或基于蛋白质聚集的心肌病。广泛的体外分子 还提出了确定TSP4协调保护性内质网应激的机制的方法 回应并有益于心脏。最后，与Kranias和Robbins实验室的大量合作是 建议确定TSP4如何影响钙处理和未折叠蛋白质的反应。

ABSTRACT The ER/SR compartment in a cardiomyocyte is highly specialized for controlling calcium fluxing in excitation- contraction coupling (ECC), as well as for regulating protein synthesis and stress responsiveness to unfolded proteins. The traditional ER stress response involves sensing of calcium and unfolded or damaged proteins in the ER through 3 distinct pathways that initiate a cascade of signaling to alter protein synthesis and other features of cellular adaptation to stress. We recently identified thrombospondin 4 (TSP4) as a stress-inducible factor that resides for a period of time in the ER/SR before being secreted to the extracellular matrix (ECM), where it alters the ER stress response. The heart expresses TSP1, TSP2, and TSP4, each of which is dramatically up-regulated following injury or stress stimulation. Interestingly, TSP4 is only expressed in heart and skeletal muscle, and it appears to be of an entirely different functional subclass from TSP1 and TSP2. We have identified a novel function for TSP4 as a cardiac inducible protein that dramatically enhances the content and function of the ER/SR resulting in greater contractility, increased activity of the adaptive ER stress response, and protection from heart failure-inducing stimuli. Thus, we hypothesize that TSP4 is a novel adaptive stress-response factor that benefits ER/SR function to provide cardioprotection. In this project we will: 1) determine if TSP4 protects the heart from failure through adaptive ER stress response pathway engagement, 2) investigate the ER stress response factors that mediate TSP4-dependent cardio-protection, and 3) determine how and where TSP4 signals the adaptive ER stress response. We will use TSP4 transgenic and gene-targeted mice to investigate these 3 specific aims, as well as numerous transgenic models with altered ER stress signaling or protein aggregation-based cardiomyopathy. Extensive in vitro molecular approaches are also proposed to identify the mechanism whereby TSP4 coordinates the protective ER stress response and benefits the heart. Finally, numerous collaborations with the Kranias and Robbins lab's are proposed to determine how TSP4 affects calcium handling and the unfolded proteins response.