Roles for TAK1 in T Cell Development, Function and Tumorigenesis

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T cell plays multiple roles in tumor biology. On one hand, T cells can become cancerous due to dysregulated proliferation and survival. On the other hand, T cell is a critical component of anti-tumor immunity that constantly surveys our body to recognize and eradicate tumor cells as "foreign" pathogens. In addition, a subset of CD4 T cells, namely regulatory T cells (Treg), potently suppresses immune cell mediated tumor rejection and thus promotes tumor outgrovi^th. To maintain a healthy, tumor-free body, the development, proliferation, survival and function of T cells have to be tightly regulated. Using a conditional gene knock-out mouse model, we have found that TGF-beta activated kinase 1 (TAKl), one of the mitogen activated protein kinase kinase kinases (MAP3K), controls virtually every aspect of T cell physiology from the development to function, potentially through regulating NFkappaB and MARK signaling pathways. To extend these studies, to investigate the underlying mechanisms by which TAKl regulates T cell function, and to test whether TAKl can potentially be an intervention target in treating various tumors/cancers in human patients, we propose to address the following specific aims: Aim 1: Further characterize mechanistically the role of TAKl in the development, homeostasis, and differentiation of T cells,. Aim 2: Address the molecular mechanisms underlying TAKl mediated common gamma chain-receptor sharing cytokine signaling in T cells. Aim 3: Investigate the feasibility of preventing/treating various tumors by targeting TAKl gene. The long term goal for this research is to elucidate how immune system is regulated, to further understand the etiology of and find the treatment of human T cell lymphomas/leukemias, and to apply the knowledge gained beyond immune sytem to aid the development of new drugs and therapies to treat various types of cancers in humans.