TNF Receptors of Colonic Epithelial Cells in IBD

描述(由申请人提供)： 肿瘤坏死因子-α(TNFpha)通过与肿瘤坏死因子受体I型(TNFR1)和II型受体(TNFR2)相关的不同信号通路诱导多种生理效应。肿瘤坏死因子α在炎症性肠病(IBD)的发病机制中起重要作用，中和治疗克罗恩病(CD)有效。炎性条件下，炎性细胞包括淋巴细胞、巨噬细胞以及结肠上皮细胞(CEC)均可表达TNFR2，而CEC上TNFR2表达的诱导与IBD的发生发展有关。在CEC上组成性表达的TNFR1似乎参与了TNFR2的表达调控。该提案中的实验旨在测试这一假设，即CEC上的TNFpha/TNFRs相互作用在功能上与免疫细胞上的相互作用在结肠炎的发展中起着不同的作用。我们还假设，在辅助性T细胞1型(Th1)和辅助性T细胞2型(Th2)显性慢性结肠炎中，TNFR介导不同的反应。在目标I中，我们计划在实验性炎症的背景下确定TNFR1和TNFR2对CEC增殖的协同作用。在AIM II中，我们计划确定CEC和巨噬细胞上的TNFR2在Th1介导的结肠炎发生中的作用。在AIM III中，我们计划确定CEC上的TNFR在Th2介导的慢性结肠炎发病机制中的作用。这些研究将有助于阐明肿瘤坏死因子/肿瘤坏死因子受体相互作用在炎症性肠病发病中的作用。 本申请是为获得临床科学家发展导师奖，申请人已完成内科培训，并接受过免疫学和免疫病理学的博士后和博士后培训。申请者的长期目标是建立并指导她自己的独立基础研究计划，将炎症性肠病的上皮生物学联系起来。因此，这些研究是由来自消化内科的Daniel K.Podolsky博士和来自麻省总医院和哈佛医学院免疫病理单元的Atul K.Bhan博士赞助的。

DESCRIPTION (provided by applicant): Tumor necrosis factor-alpha (TNFalpha) induces multiple physiological effects through distinct signaling cascades associated with TNF receptor-type I (TNFR1) and -type II (TNFR2). TNFalpha plays an important role in the pathogenesis of inflammatory bowel disease (IBD) and neutralization of TNFalpha is effective in the treatment of Crohn's disease (CD). TNFR2 can be expressed by inflammatory cells including lymphocytes and macrophages as well as colonic epithelial cells (CEC) under inflammatory conditions, and the induction of TNFR2 expression on CEC is associated with the development of IBD. TNFR1 which is constitutively expressed on the CEC seems to be involved in the regulation of TNFR2 expression. The experiments in the proposal are designed to test the hypothesis that TNFalpha/TNFRs interactions on CEC play functionally distinct roles from those on immune cells in the development of colitis. We also hypothesize that the TNFRs mediate different responses in T helper type 1 (Th1)- and T helper type 2 (Th2)-dominant chronic colitis. In Aim I, we plan to define the cooperative effect of TNFR1 and TNFR2 on the CEC proliferation in the context of experimental inflammation. In Aim II, we plan to define the role of TNFR2 on CEC and macrophages in the development of Th1-mediated colitis. In Aim III, we plan to define the role of TNFRs on CEC in the pathogenesis of Th2-mediated chronic colitis. These studies will help clarify the functional role of TNF/TNFRs interaction on CEC in the pathogenesis of IBD. This application is for a Mentored Clinical Scientist Development Award to an applicant who has completed training in internal medicine, and has received pre-and post-doctoral training in Immunology and immunopathology. The applicant's long term goals are to establish and direct her own independent basic research program in studies to link epithelial biology in inflammatory bowel disease. Accordingly, these studies are sponsored by Dr. Daniel K. Podolsky from the Division of Gastroenterology and by Dr. Atul K. Bhan from the Immunopathology Unit, both at Massachusetts General Hospital and Harvard Medical School.