Regulation of TCR signaling by a novel enzyme activity.

描述（由申请人提供）：T细胞自身反应性是许多自身免疫性疾病的核心，它源于允许T细胞产生有效免疫应答的特性。因此，要了解不同的自身免疫性疾病的病因，需要对控制T细胞活化的机制有全面和综合的了解。我研究的长期目标是了解T细胞反应性的生物化学。目前，我的实验室正在研究两种相关的蛋白质Sts-1和Sts-2如何协同作用来负调节T细胞信号通路。Sts-1和Sts-2在控制TCR信号通路中的作用是通过一种缺乏Sts基因的小鼠来揭示的。来自Sts- 1/2-/-小鼠的T细胞响应于TCR刺激而显著过度增殖。在多发性硬化症小鼠模型中，这种过度增殖表型伴随着TCR下游信号传导途径的激活增加、细胞因子产生水平升高以及Sts-1/2-/-小鼠对自身免疫的易感性增加。在我们正在进行的Sts蛋白功能的研究中，我们最近发现Sts-1具有一种新的和有效的酶活性。这种活性源自蛋白质内的进化保守区域，我们最近的数据表明，它在Sts-1调节TCR信号通路的能力中起着重要作用。Sts-1与其他已知的酶非常不同，使其成为一种新的独特的磷酸酶。此外，Sts-1催化活性和调节T细胞活化之间的联系尚不清楚，也未探索。本提案中概述的实验旨在阐明这些领域。我们的具体目标是：1。确定定义和调节Sts-1催化活性的结构特征。2.研究Sts-1磷酸酶活性在Zap-70信号转导中的作用。我们将使用一些最近开发的协议来实现我们的目标。本文所述研究的完成将帮助我们建立Sts-1如何与Sts-2和其他细胞内信号传导机制合作以控制T细胞反应性的模型。我们希望，对控制T细胞活化的所有机制的广泛、综合的理解将转化为预防各种自身免疫性疾病发作的疗法。当免疫系统内的正常调节机制失效时，就会出现自身免疫疾病。开发将预防或治愈自身免疫性疾病的疗法将需要对控制免疫反应的机制有全面和综合的了解。该项目的重点是了解一种参与调节T细胞活化的新型蛋白质的功能。

DESCRIPTION (provided by applicant): The T cell auto-reactivity that lies at the heart of many autoimmune diseases arises from the very properties that allow T cells to mount an effective immune response. Thus, to understand the etiology of different autoimmune diseases will require a thorough and integrated understanding of the mechanisms that control T cell activation. The long-term objective of my research is to understand the biochemistry of T cell reactivity. Currently, my laboratory is studying how two related proteins, Sts-1 and Sts-2, act in concert to negatively regulate T cell signaling pathways. The role of Sts-1 and -2 in controlling TCR signaling pathways was revealed by a strain of mice engineered to lack the Sts genes. T cells from Sts- 1/2-/- mice dramatically hyper-proliferate in response to TCR stimulation. This hyper-proliferative phenotype is accompanied by increased activation of signaling pathways downstream of the TCR, elevated levels of cytokine production, and increased susceptibility of Sts-1/2-/- mice to autoimmunity in a mouse model of multiple sclerosis. In our ongoing effort to characterize the functions of the Sts proteins, we recently discovered that Sts-1 has a novel and potent enzyme activity. This activity derives from an evolutionarily conserved region within the protein and our recent data indicates that it plays an essential role in the ability of Sts-1 to regulate TCR signaling pathways. Sts-1 is sufficiently dissimilar to other known enzymes to make it a novel and unique phosphatase. In addition, the connection between Sts-1 catalytic activity and regulation of T cell activation in unknown and unexplored. The experiments outlined in this proposal are designed to shed light on these areas. Our Specific Aims are: 1. To determine the structural features that define and regulate Sts-1 catalytic activity. 2. To determine the role of Sts-1 phosphatase activity in regulating Zap-70 signaling. We will use some recently developed protocols to accomplish our goals. Completion of the studies described herein will help us build a model of how Sts-1 cooperates with Sts-2 and other intracellular signaling mechanisms to control T cell reactivity. It is our hope that a broad, integrated understanding of all the mechanisms that control T cell activation will translate into therapies that prevent the onset of a variety of autoimmune diseases. Autoimmune diseases arise when normal regulatory mechanisms within the immune system fail. Developing therapies that will prevent or cure autoimmune diseases will require a thorough and integrated understanding of the mechanisms that control the immune response. This project focuses on understanding the function of a novel protein that participates in the regulation of T cell activation.