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导致个体残疾、生活质量下降、无法自我维持以及社会和医疗保健系统经济负担沉重的严重疾病。本申请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错误定向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，我们最近鉴定了肌醇（1，4，5）三磷酸-3-激酶B（Itpk B）作为T细胞发育的新调节剂。我们的突变小鼠之一，T-少女士，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似乎只需要阳性选择。我们的初步数据表明，它作为一种新的调节Ras通过第二信使IP 3转化为“第三信使”，IP 4。因此，我们的研究结果不仅揭示了一种新的调节T细胞发育，而且还揭示了一种新的调节癌基因Ras和新的生物学原理，即使用IP 4来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。因此，Itpk在信号传导中的作用很可能具有广泛的意义。上游机制的定义，ItpkB调节，下游机制，ItpkB管理积极的选择，因此，将促进我们的淋巴细胞发育和潜在的自身免疫或免疫缺陷缺陷的机制的理解。此外，通过确定ItpkB如何调节癌基因Ras，我们的研究将揭示潜在参与癌症的新机制。为了了解ItpkB如何进行这些有趣的功能，我们建议（目的1）分析ItpkB在胸腺细胞选择过程中的TCR信号转导中的功能，（目的2）分析胸腺细胞中ItpkB下游的特异性信号转导途径，（目的3）分析胸腺细胞中ItpkB的上游调控机制。这些研究与一般的信号转导、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如何进行其有趣的功能，我们提出（目的1）分析ItpkB在胸腺细胞选择过程中TCR信号传导中的功能，（目的2）分析胸腺细胞ItpkB下游特异性信号通路;（目的3）分析胸腺细胞ItpkB的上游调控机制。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。

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.