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

说明(申请人提供)：免疫缺陷和自身免疫是一种严重的疾病，会导致个体残疾、生活质量下降、无法自我维持，并给社会和卫生保健系统带来沉重的经济负担。这项应用的长期目标是帮助更好地了解这些严重疾病背后的病理机制。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查中，我们最近发现肌醇(1，4，5)三磷酸-3-激酶B(ItpkB)是一种新的T细胞发育调节因子。我们的一个小鼠突变体，T-less女士，由于胸腺细胞成熟受损和ItpkB缺乏而缺乏外周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。与大多数参与胸腺细胞发育的已知分子形成鲜明对比的是，ItpkB似乎只是正向选择所必需的。我们的初步数据表明，它通过将第二信使IP3转化为“第三信使”IP4来作为RAS的新型调节因子。因此，我们的结果不仅揭示了一种新的T细胞发育调节因子，还揭示了癌基因RAS的一种新调节因子，以及使用IP4调节许多不同信号级联下游许多不同细胞类型的基本信号过程的新生物学原理。因此，Itpks在信号转导中的作用很可能具有广泛的意义。ItpkB上游调控机制和ItpkB调控正选择的下游机制的定义，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械性理解。此外，通过定义ItpkB如何调控癌基因RAS，我们的研究将揭示潜在参与癌症的新机制。为了了解ItpkB如何执行这些有趣的功能，我们建议(1)分析ItpkB在胸腺细胞选择过程中TCR信号转导中的作用，(2)分析胸腺细胞中ItpkB下游的特定信号通路，(3)分析胸腺细胞中调节ItpkB的上游机制。这些研究与信号转导、T细胞受体信号转导、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(1)分析ItpkB在胸腺细胞选择过程中TCR信号转导中的功能，(2)分析ItpkB下游在胸腺细胞中的特定信号通路，(3)分析胸腺细胞中调节ItpkB的上游机制。这些研究通常与信号转导、T细胞受体信号转导、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。

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.