Innate/Adaptive Immune Interactions in Gut Inflammation

描述（由申请人提供）：当前项目资助的总体主题是确定肠道内先天免疫系统如何通知适应性免疫系统，以及这种相互作用中的错误沟通如何导致IBD的发展。我们目前资助的资助重点是lEC在调节健康和疾病中的先天和适应性免疫反应中的作用。虽然上皮细胞将继续是这一更新的突出焦点，但迄今为止产生的数据已使该项目朝着研究Th17反应调控的方向发展，Th17反应是参与粘膜炎症的关键细胞类型。所有项目的目标都涉及使用小鼠和人类模型，使研究人员能够在人体组织中进行观察，然后在小鼠中建立模型，反之亦然（通过动物模型研究获得的结果可以通过研究人体组织来验证）。在第一个项目中，重点是评估新定义的角色

DESCRIPTION (provided by applicant): The overarching theme of the current program project grant is to define how the innate immune system informs the adaptive immune system in the intestine and how miscommunication in this interaction results in the development of IBD. Our currently funded grant has a strong emphasis on the role of the lEC in regulating innate and adaptive Immune responses in health and disease. While the epithelial cell will continue to be a prominent focus in this renewal, the data generated thus far have allowed the projects to evolve in the direction of studying the regulation of Th17 responses, a key cell type involved in mucosal inflammation. All projects have aims that involve the use of mouse and human models allowing the investigators to make observations in human tissues that can then be modeled in the mouse and vice versa (results obtained through the study of animal models can be validated by studying human tissues). In the first project the focus is on assessing the role of a newly defined population that expresses both FoxP3 and IL-17 in Crohn's disease tissues and may represent the previously undescribed interface between Tregs and Th17 cells. The second project focuses on the transcription factor associated with Th17 development, ROR?t, by analyzing the contributions of chemokines in driving these cells to the gut (an extension of the previous granting period) and the role that IL23 plays in the development of Th17 mediated inflammation (taking advantage of murine models developed by the PI). The third project also reflects the evolution of studies from the first granting period by studying the role of the transcription facto IRF8 (ICSBP) on Th17 differentiation (acting as a negative regulator of IL17 production and ROR?t function) and its role in IBD pathogenesis. The fourth project is new to this PPG but takes advantage of the growth of mucosal immunology at Mount Sinai. Dr. Julie Blander studies the role of TLR signaling in Th17 responses in vitro and in vivo using infected vs. uninfected apoptic cells including an infection model (C. rodentium). Her studies fit perfectly with the other projects in our program and her participation in the group provides her access to unique resources to study murine and human IBD. At the same time, she provides models (C. rodentium) that will be helpful for the other PPG members. Overall the focus and interactive nature of the program (20 joint publications in 4 years, 3 additional NIH grants on related areas) provide a solid basis for a productive outcome. PUBLIC HEALTH RELEVANCE: The studies detailed in this proposal focus new light on a pathway involved in mediating mucosal inflammation. It has direct relevance to IBD pathogenesis and may add new insights leading to novel therapies. TABLE OF CONTENTS Overall Description 2