Roles for TAK1 in T cell development, function and tumorigenesis

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DESCRIPTION (provided by applicant): 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 outgrowth. 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 (TAK1), 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 MAPK signaling pathways. To extend these studies, to investigate the underlying mechanisms by which TAK1 regulates T cell function, and to test whether TAK1 can potentially be an intervention target in treating various tumors/cancers in human patients, we propose to address the following specific aims: Specific Aim 1: Further characterize mechanistically the role of TAK1 in the development, homeostasis, and differentiation of T cells. Specific Aim 2: Address the molecular mechanisms underlying TAK1 mediated common gamma chain-receptor sharing cytokine signaling in T cells. Specific Aim 3: Investigate the feasibility of preventing/treating various tumors by targeting TAK1 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 system to aid the development of new drugs and therapies to treat various types of cancers in humans. Cancer is a disease afflicting millions of people. Immune cells, such as T cells, can become cancerous and are also critical for eradicating tumors. This study would help us to understand the roles for T cell in tumorigensis and aid our effort of designing innovative drugs/therapies against various types of cancers.