Immunogenetic Mechanisms of Experimental Crohn's Disease

描述（由申请人提供）： 克罗恩病（CD）是一种使人衰弱的慢性疾病，目前尚无治愈方法。虽然有证据表明涉及遗传、免疫和环境机制，但CD的确切原因仍不清楚。间接证据表明，CD可能是由遗传易感宿主对“未知”抗原的先天免疫应答失调引发的。此次竞争性更新的主要优势在于独特的SAMP 1/YitFc（SAMP）小鼠模型，该模型在上一个资助期内已被我们的团队广泛表征，以及该计划的高度协同性。本延续计划的总体目标是研究CD自发小鼠模型的关键致病机制。该计划项目将继续由Fabio Cominell博士指导，并将包括5个项目和2个核心。由Cominelli博士领导的项目1将重点关注关键细胞因子在该模型中介导慢性肠道炎症的作用。项目二， 由Marcia McDuffie博士领导的研究小组将根据上一个资助期确定的染色体位点，确定SAMP小鼠中与回肠炎易感性有关的易感基因。由Steven Cohn博士领导的项目3将研究Paneth细胞及其防御素在引发回肠炎中的作用。由Klaus Ley博士领导的项目4将研究SAMP小鼠中淋巴细胞归巢和运输的机制，特别关注L-选择素和PSGL-1。项目5是由Theresa Pizarro博士领导的一个新项目，将研究上皮先天免疫反应在SAMP小鼠中引发和维持回肠炎的作用。该计划由一个协调该计划的行政核心和一个动物中心支持。 核心，集中生产和育种的SAMP小鼠和其他同类系。该计划项目的长期目标是了解实验性CD的关键致病机制，以帮助开发治疗至少一组患有这种毁灭性疾病的患者的方法。

DESCRIPTION (provided by applicant): Crohn's disease (CD) is a debilitating chronic condition with no known cure. Although there is evidence for the involvement of genetic, immunological, and environmental mechanisms, the precise cause(s) of CD remain unclear. Indirect evidence suggest that CD may be initiated by a dysregulated innate immune response against an "unknown" antigen in a genetically susceptible host. The major strengths of this competitive renewal are the unique SAMP1/YitFc (SAMP) mouse model, which has been extensively characterized by our group during the last funding period, and the highly synergistic nature of the program. The overall objective of this continuation proposal is to investigate the key pathogenic mechanisms underlying this spontaneous murine model of CD. The Program Project will continue to be directed by Dr. Fabio Cominell, and will consist of 5 projects and 2 cores. Project 1, headed by Dr. Cominelli, will extend its focus on the role of pivotal cytokines in mediating chronic intestinal inflammation in this model. Project 2, headed by Dr. Marcia McDuffie, will identify susceptibility genes involved in the predisposition to ileitis in SAMP mice based on the chromosomal loci identified during the previous funding period. Project 3, headed by Dr. Steven Cohn, will investigate the role of Paneth cells and their defensins in initiating ileitis. Project 4, headed by Dr. Klaus Ley, will study the mechanisms of lymphocyte homing and trafficking in SAMP mice, with a particular focus on L-selectin and PSGL-1. Project 5, a new project headed by Dr. Theresa Pizarro, will investigate the role of epithelial innate immune responses in initiating and perpetuating ileitis in SAMP mice. This Program is supported by an Administrative Core, which coordinates the program, and an Animal Core, which centralizes the production and breeding of SAMP mice and other congenic lines. The long-term goal of this Program Project is to understand the key pathogenic mechanisms of experimental CD, to aid development of a cure for at least a subgroup of patients with this devastating disease.