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.
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