Inositol-Trisphosphate Kinase B (ItpkB) in T Cell Development and Function

肌醇三磷酸激酶 B (ItpkB) 在 T 细胞发育和功能中的作用

• 批准号: 8212138
• 负责人: Karsten Sauer
• 金额: $ 46.43万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212138
• 关键词: Autoimmune Diseases; Autoimmunity; Binding; Biological; Cells; Data; Defect; Development; Disease; Economic Burden; Figs - dietary; Future; Genetic; Genetic Screening; Graft Rejection; Healthcare Systems; Immune system; Immunologic Deficiency Syndromes; In Vitro; Individual; Inositol; Jurkat Cells; Ligands; Lymphocyte; Malignant Neoplasms; Modeling; Mus; Mutant Strains Mice; N-terminal; PH Domain; Peptides; Peripheral; Phosphotransferases; Progress Reports; Publications; Publishing; Quality of life; Receptor Signaling; Regulation; Research; Research Design; Research Methodology; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Societies; System; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Text; Thymocyte Development; Thymocyte Selection; TimeLine; Update; Work; base; cell type; computerized data processing; disability; novel; ras Oncogene; second messenger; thymocyte

DESCRIPTION (provided by applicant): Immunodeficiency and autoimmunity are serious disorders contributing to individual disability, loss of quality of life, inability to self-sustain, and high economic burden for society and health care system. The long-term objective of this application is to contribute to a better understanding of the pathological mechanisms underlying these serious disorders. Defects in lymphocyte development are a major cause for immunodeficiency and autoimmunity through impaired or misdirected function of the adaptive immune system. In a forward genetic screen in mice, we recently identified Inositol(1,4,5)trisphosphate-3-kinase B (ItpkB) as a novel regulator of T cell development. One of our mouse mutants, Ms. T-less, lacks peripheral T cells due to impaired thymocyte maturation and ItpkB deficiency. Perturbed ItpkB function could thus underlie immunodeficiency or autoimmune disease. In stark contrast to most known molecules involved in thymocyte development, ItpkB appears exclusively required for positive selection. Our preliminary data suggest that it acts as a novel regulator of Ras via conversion of the second messenger IP3 into a "third messenger", IP4. Thus, our results not only unveiled a novel regulator of T cell development, but also a novel regulator of the oncogene Ras and the novel biological principle of using IP4 to regulate a fundamental signaling process operative in many different cell types downstream of many different signaling cascades. The role of Itpks in signaling is thus very likely of broad significance. Definition of the upstream mechanisms regulating ItpkB, and of the downstream mechanisms by which ItpkB governs positive selection, will thus promote our mechanistic understanding of lymphocyte development and of potential defects underlying autoimmunity or immunodeficiency. In addition, via defining how ItpkB regulates the oncogene Ras, our studies will unveil novel mechanisms potentially involved in cancer. To understand how ItpkB conducts these intriguing functions, we propose to (Aim 1) analyze the function of ItpkB in TCR signaling during thymocyte selection, (Aim 2) analyze the specific signaling pathways downstream of ItpkB in thymocytes and (Aim 3) analyze the upstream mechanisms which regulate ItpkB in thymocytes. These studies are highly relevant for the fields of Signal Transduction in general, T cell receptor signaling, T cell development, Autoimmune Disease, Immunodeficiency, Transplant Rejection and Cancer.To understand how ItpkB conducts its intriguing functions, we propose to (Aim 1) analyze the function of ItpkB in TCR signaling during thymocyte selection, (Aim 2) analyze the specific signaling pathways downstream of ItpkB in thymocytes and (Aim 3) analyze the upstream mechanisms which regulate ItpkB in thymocytes. These studies are highly relevant for the fields of Signal Transduction in general, T cell receptor signaling, T cell development, Autoimmune Disease, Immunodeficiency, Transplant Rejection and Cancer.

描述（由申请人提供）：免疫缺陷和自身免疫是导致个人残疾、生活质量下降、无法自我维持以及给社会和医疗保健系统造成沉重经济负担的严重疾病。该应用的长期目标是有助于更好地了解这些严重疾病的病理机制。淋巴细胞发育缺陷是通过适应性免疫系统功能受损或误导而导致免疫缺陷和自身免疫的主要原因。在小鼠的正向遗传筛选中，我们最近发现肌醇(1,4,5)三磷酸-3-激酶 B (ItpkB) 是 T 细胞发育的新型调节剂。我们的小鼠突变体之一，Ms. T-less，由于胸腺细胞成熟受损和 ItpkB 缺陷而缺乏外周 T 细胞。因此，ItpkB 功能紊乱可能是免疫缺陷或自身免疫性疾病的基础。与大多数已知的参与胸腺细胞发育的分子形成鲜明对比的是，ItpkB 似乎是正选择所必需的。我们的初步数据表明，它通过将第二信使 IP3 转换为“第三信使”IP4，充当 Ras 的新型调节剂。因此，我们的结果不仅揭示了 T 细胞发育的新型调节剂，而且还揭示了癌基因 Ras 的新型调节剂，以及使用 IP4 调节在许多不同信号级联下游的许多不同细胞类型中起作用的基本信号传导过程的新生物学原理。因此，Itpks 在信号传导中的作用很可能具有广泛的意义。定义调节 ItpkB 的上游机制以及 ItpkB 控制正选择的下游机制，将促进我们对淋巴细胞发育和自身免疫或免疫缺陷潜在缺陷的机制理解。此外，通过定义 ItpkB 如何调节癌基因 Ras，我们的研究将揭示可能与癌症相关的新机制。为了了解 ItpkB 如何发挥这些有趣的功能，我们建议（目标 1）分析胸腺细胞选择过程中 ItpkB 在 TCR 信号传导中的功能，（目标 2）分析胸腺细胞中 ItpkB 下游的特定信号通路，（目标 3）分析胸腺细胞中调节 ItpkB 的上游机制。这些研究与一般信号转导、T 细胞受体信号传导、T 细胞发育、自身免疫性疾病、免疫缺陷、移植排斥和癌症等领域高度相关。为了了解 ItpkB 如何发挥其有趣的功能，我们建议（目标 1）分析 ItpkB 在胸腺细胞选择过程中 TCR 信号传导中的功能，（目标 2）分析 ItpkB 下游的特定信号通路 胸腺细胞并（目标 3）分析胸腺细胞中调节 ItpkB 的上游机制。这些研究与一般信号转导、T 细胞受体信号传导、T 细胞发育、自身免疫性疾病、免疫缺陷、移植排斥和癌症等领域高度相关。