Protein Phosphatases in Lymphocyte Signal Transduction

淋巴细胞信号转导中的蛋白磷酸酶

• 批准号: 7204167
• 负责人: Tse-Hua Tan
• 金额: $ 35.56万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7204167
• 关键词: Ablation; Antibody Formation; Apoptosis; Autoimmunity; Biochemical Genetics; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation; Cell Proliferation Regulation; Cell physiology; Cells; Centrosome; Collagen Arthritis; Disease; Evaluation; Experimental Arthritis; Experimental Autoimmune Encephalomyelitis; Future; Gene Targeting; Genetic Recombination; Immune System Diseases; Immune response; Immunization; Infection; Inflammatory Response; Ink; Integration Host Factors; Knock-out; Knockout Mice; Lead; Lymphocyte; MAPK8 gene; Mediating; Modeling; Mus; NF-kappa B; Okadaic Acid; Pathway interactions; Phosphoric Monoester Hydrolases; Physiological; Protein Phosphatase 2A Regulatory Subunit PR53; Protein Serine/Threonine Phosphatase; Protein phosphatase; Retroviridae; Role; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; System; T-Cell Activation; T-Cell Development; T-Cell Proliferation; T-Lymphocyte; Testing; Th1/Th2 Differentiation Pathway; Therapeutic Agents; Transgenic Mice; base; cell mediated immune response; design; embryonic stem cell; in vivo; leukemia/lymphoma; mouse model; novel

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.

描述（由申请人提供）：INK和NF-κ B参与T细胞活化/分化、炎症反应、凋亡和细胞增殖。蛋白磷酸酶4（PP 4）是冈田酸敏感的蛋白丝氨酸/苏氨酸磷酸酶。迄今为止，人们对PP 4的功能知之甚少。我们的研究结果为PP 4/JNK和PP 4/ NF-kappaB模块的存在提供了第一个证据，作为控制T细胞信号通路的新范例。了解PP 4介导的T细胞信号转导的潜在机制将有助于发现PP 4的功能。本申请计划研究PP 4在T细胞信号传导和T细胞介导的免疫应答中的作用。为了揭示PP 4在T细胞中的新的生理功能，我们将使用Cre-foxP重组系统和Lck-Cre转基因小鼠产生PP 4敲除细胞和小鼠。这些方法是：（i）利用各种生物化学和遗传学方法了解PP 4在T细胞增殖、凋亡、分化、中心体功能和信号传导中的作用;（ii）研究PP 4在Th 1/Th 2分化、免疫应答和自身免疫中的体内功能。最终，我们计划解剖各种PP 4介导的信号通路在免疫反应，白血病/淋巴瘤和免疫疾病。我们未来对PP 4介导的淋巴细胞信号通路中所涉及的宿主因素的了解将为白血病/淋巴瘤、感染和免疫性疾病（如自身免疫）的有效细胞内治疗剂的发现、设计和评价提供基本信息。具体目标是：目标1。使用PP 4条件性敲除小鼠和细胞研究PP 4在T细胞增殖、凋亡、分化和信号传导中的作用。目标二。使用T细胞特异性PP 4条件性敲除小鼠研究PP 4在T细胞介导的免疫应答和自身免疫中的体内功能。