Protein Phosphatases in Lymphocyte Signal Transduction

描述(申请人提供)：墨水和核因子-kappaB参与T细胞的激活/分化、炎症反应、细胞凋亡和细胞增殖。蛋白磷酸酶4(PP4)是一种冈田酸敏感的丝氨酸/苏氨酸磷酸酶。迄今为止，人们对PP4的功能知之甚少。我们的结果首次证明了PP4/JNK和PP4/NF-kappaB模块作为控制T细胞信号通路的新范式的存在。了解PP4介导的T细胞信号转导的潜在机制将有助于发现PP4的功能。这项应用计划研究PP4在T细胞信号和T细胞介导的免疫反应中的作用。为了揭示PP4在T细胞中的新的生理功能，我们将利用Cre-FoxP重组系统和Lck-Cre转基因小鼠产生PP4基因敲除细胞和小鼠。这些途径包括：(I)利用各种生化和遗传学手段了解PP4在T细胞增殖、凋亡、分化、中心体功能和信号转导中的作用；(Ii)研究PP4在体内Th1/Th2分化、免疫反应和自身免疫中的作用。最终，我们计划剖析免疫反应、白血病/淋巴瘤和免疫性疾病中PP4介导的各种信号通路。我们未来对PP4介导的淋巴细胞信号通路中涉及的宿主因素的了解将为发现、设计和评估有效的白血病/淋巴瘤、感染和免疫疾病(如自身免疫)的细胞内治疗药物提供基础信息。目的：1.利用PP4条件性基因敲除小鼠和细胞，研究PP4在T细胞增殖、凋亡、分化和信号转导中的作用。目的2.利用T细胞特异性PP4条件性基因敲除小鼠，研究PP4在T细胞介导的免疫反应和自身免疫中的作用。

DESCRIPTION (provided by applicant): INK and NF-kappaB are involved in T-cell activation/differentiation, inflammatory responses, apoptosis, and cell proliferation. Protein phosphatase 4 (PP4) is an okadaic acid-sensitive protein serine/threonine phosphatase. To date, little is known about the functions of PP4. Our results provide the first evidence for the existence of PP4/JNK and PP4/ NF-kappaB modules as a new paradigm for the control of the signaling pathways in T cells. Understanding the underlying mechanisms of PP4-mediated T-cell signal transduction will lead to the discovery of the functions of PP4. This application plans to study the roles of PP4 in T-cell signaling and T-cell mediated immune responses. To unveil novel physiological functions of PP4 in T cells, we will generate PP4 knockout cells and mice using the Cre-foxP recombination system and Lck-Cre transgenic mice. The approaches are: (i) to understand the roles PP4 in T-cell proliferation, apoptosis, differentiation, centrosome function, and signaling using various biochemical and genetic approaches, and (ii) to study the in vivo functions of PP4 in Th1/Th2 differentiation, immune responses, and autoirnmunity. Ultimately, we plan to dissect various PP4-mediated signaling pathways in immune responses, leukemia/lymphoma, and immunological diseases. Our future understanding of host factors involved in the PP4-mediated lymphocyte signaling pathways will provide information fundamental to the discovery, design, and evaluation of effective intracellular therapeutic agents for leukemia/lymphoma, infections, and immunological disorders such as autoimmunity. The specific aims are: Aim 1. Study the roles of PP4 in T-cell proliferation, apoptosis, differentiation, and signaling using PP4 conditional knockout mice and cells. Aim 2. Study in vivo functions of PP4 in T-cell mediated immune responses and autoimmunity using Tcell specific PP4 conditional knockout mice.