Autophagy and Crohn's Disease

描述（由申请人提供）：该挑战项目基于(a)我们关于IRGM作为自噬因子1的开创性工作，以及(b)自噬和IRGM在克罗恩病中的作用的遗传关联识别2。主要目的有两个：(I)描述自噬在克罗恩病病因和发病机制中的作用，（II）在细胞水平上确定IRGM亚型作用的具体机制。该挑战项目将在两年内：(a)推进免疫、传染病和慢性炎症性疾病中自噬的整个领域，特别强调粘膜免疫和肠道炎症；(b)填补关于人类自噬基因多态性如何易患炎症性肠病（即克罗恩病）的特定知识空白。所提议的关系可以并且将在两年内经受考验。在本次资助结束时，我们将获得(i)对自噬如何在与IBD相关的粘膜免疫中起作用的全新视角的理解，以及（ii）关于IRGM在克罗恩病中的作用的非常具体的知识。该项目的结果不仅将提高我们对自噬在粘膜免疫和IBD中的作用的理解，而且将为在克罗恩病的临床试验中重新使用安全药物雷帕霉素建立一个令人信服的案例。[1]李建军，李建军，李建军，等。人IRGM诱导细胞内分枝杆菌自噬的研究。科学，313,1438-1441（2006）。2 Parkes， M.等。自噬基因IRGM和多个其他复制位点的序列变异有助于克罗恩病的易感性。生物医学工程学报，39(2007):830-832。

DESCRIPTION (provided by applicant): This challenge project is based on (a) our pioneering work on IRGM as an autophagy factor 1, and (b) the genetic linkage recognition 2 of the role of autophagy and IRGM in Crohn's disease. The main objective is two-fold: (I) to delineate the role of autophagy in Crohn's disease etiology and pathogenesis, and (II) to determine specifically the mechanism of IRGM isoform action at the cellular level. This challenge project will in two years: (a) move forward the entire field of autophagy in immunity, infectious disease, and chronic inflammatory illnesses, with a special emphasis on mucosal immunity and inflammation of the gut, and (b) close a specific knowledge gap on how autophagy genetic polymorphisms in human populations predispose to the prevalent form of inflammatory bowel disease (IBD) known as Crohn's disease. The proposed relationships can and will be tested in 2 years. At the end of this grant we will have (i) a whole new view understanding of how autophagy works in mucosal immunity in association with IBD, and (ii) very specific knowledge regarding what role IRGM plays in Crohn's disease. Not only will the results of this project improve our understanding of the role of autophagy in mucosal immunity and IBD, but a compelling case will be built for the repurposing of the safe drug rapamycin for clinical trials in Crohn's disease. 1 Singh, S.B., Davis, A.S., Taylor, G.A. & Deretic, V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313, 1438-1441 (2006). 2 Parkes, M. et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet 39, 830-832 (2007) PUBLIC HEALTH RELEVANCE: In the US, 500,000 people are suffering from Crohn's disease, a debilitating chronic inflammatory illness of the intestine that often requires surgery due to intestinal obstruction. We had been studying a gene called IRGM before it was linked through genetic studies with Crohn's disease. We discovered that this gene controls a process called autophagy that acts to cleanse the interior of all cells in our body, including those of the gut, and rids them of festering intracellular bacteria and inflammatory microbial products. In this project, we will determine how mutations in the IRGM gene in patients with Crohn's disease affect autophagy, and how this leads to inflammation of the intestine and progressive tissue pathology and destruction. We will be able to decipher this in a 2 year time period by studying blood cells and surgical resection tissues from the gut of Crohn's disease patients and analyzing IRGM function in autophagy in these specimens. As a final product two years from now, based on the knowledge acquired through this work, doctors will be able to begin clinical trials with currently existing FDA approved drugs to increase or decrease autophagy in patients, and help cure those afflicted by Crohn's disease.