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

描述（由申请人提供）：免疫缺陷和自身免疫是严重的疾病，会导致个人残疾，生活质量下降，无法自我维持，给社会和医疗保健系统带来很高的经济负担。这项应用的长期目标是有助于更好地理解这些严重疾病背后的病理机制。淋巴细胞发育缺陷是适应性免疫系统功能受损或定向错误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细胞发育的一种新的调节因子。我们的一种小鼠突变体，Ms. T-less，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。与大多数已知参与胸腺细胞发育的分子形成鲜明对比的是，ItpkB似乎只需要正选择。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，作为Ras的一种新型调节剂。因此，我们的研究结果不仅揭示了一种新的T细胞发育调节剂，还揭示了一种新的癌基因Ras调节剂，以及利用IP4调节许多不同细胞类型中许多不同信号级联下游的基本信号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。定义调控ItpkB的上游机制，以及ItpkB调控正向选择的下游机制，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，通过确定ItpkB如何调节致癌基因Ras，我们的研究将揭示可能涉及癌症的新机制。为了了解ItpkB如何发挥这些有趣的功能，我们提出（目标1）分析ItpkB在胸腺细胞选择过程中在TCR信号传导中的功能，（目标2）分析ItpkB在胸腺细胞中下游的特定信号通路，（目标3）分析ItpkB在胸腺细胞中调控的上游机制。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，我们提出（目标1）分析ItpkB在胸腺细胞选择过程中在TCR信号传导中的功能，（目标2）分析ItpkB在胸腺细胞中下游的特定信号通路，（目标3）分析ItpkB在胸腺细胞中调控的上游机制。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。

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.