TNF Receptors of Colonic Epithelial Cells in IBD

描述（由申请人提供）： 肿瘤坏死因子-α（TNF α）通过与TNF受体-I型（TNFR 1）和-II型（TNFR 2）相关的不同信号级联诱导多种生理效应。TNF α在炎症性肠病（IBD）的发病机制中起重要作用，中和TNF α在克罗恩病（CD）的治疗中是有效的。TNFR 2可在炎症条件下由包括淋巴细胞和巨噬细胞的炎性细胞以及结肠上皮细胞（CEC）表达，并且CEC上TNFR 2表达的诱导与IBD的发展相关。在CEC上组成性表达的TNFR 1似乎参与TNFR 2表达的调节。该提案中的实验旨在检验CEC上的TNF α/TNFRs相互作用在结肠炎发展中与免疫细胞上的相互作用在功能上不同的假设。我们还假设TNFRs介导T辅助细胞1型（Th 1）和T辅助细胞2型（Th 2）占主导地位的慢性结肠炎的不同反应。在目的I中，我们计划在实验性炎症的背景下确定TNFR 1和TNFR 2对CEC增殖的协同作用。在目的II中，我们计划确定TNFR 2对CEC和巨噬细胞在Th 1介导的结肠炎发展中的作用。在目的III中，我们计划确定CEC上的TNFRs在Th 2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TNF/TNFRs相互作用对CEC在IBD发病机制中的功能作用。 本申请是指导临床科学家发展奖的申请人谁已经完成了内科培训，并已接受了免疫学和免疫病理学的博士前和博士后培训。申请人的长期目标是建立和指导她自己的独立基础研究计划，研究炎症性肠病中的上皮生物学。因此，这些研究由Dr.丹尼尔K申办。消化科的Podolsky和Atul K.来自马萨诸塞州总医院和哈佛医学院免疫病理科的巴恩。

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.