Roles for TAK1 in T Cell Development, Function and Tumorigenesis

T细胞在肿瘤生物学中发挥着多种作用。一方面，T细胞可能由于调节失调而癌变 扩散和生存。另一方面，T细胞是抗肿瘤免疫的关键组成部分， 不断地检查我们的身体，以识别和根除肿瘤细胞作为“外来”病原体。此外，一个子集 CD4T细胞，即调节性T细胞(Treg)，有效地抑制免疫细胞介导的肿瘤排斥反应和 从而促进肿瘤的生长。为了保持健康、无肿瘤的身体，发育、增殖、 T细胞的生存和功能必须受到严格的调控。使用条件基因敲除小鼠模型，我们 已发现转化生长因子-β激活的蛋白激酶1(Tak1)，一种丝裂原活化的蛋白激酶 (MAP3K)，几乎控制着T细胞生理的方方面面，从发育到功能，潜在地 通过调节NFkappaB和MARK信号通路。为了扩展这些研究，调查 Takl调节T细胞功能的潜在机制，并测试Takl是否可能成为一种 针对人类患者的各种肿瘤/癌症的干预目标，我们建议解决以下问题 具体目标： 目标1：进一步从机制上描述Tak1在发育、动态平衡和 T细胞的分化。 目的2：探讨Tak1介导的共同伽马链受体共享的分子机制 T细胞中的细胞因子信号转导。 目的3：探讨靶向Tak1基因防治多种肿瘤的可行性。 这项研究的长期目标是阐明免疫系统是如何调节的，以进一步了解 人类T细胞淋巴瘤/白血病的病因和治疗方法，并应用所获得的知识 Beyond免疫系统帮助开发新药和疗法来治疗各种类型的癌症 人类。

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.