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连锁识别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，以及(Ii)在细胞水平上明确IRGM异构体的作用机制。这一挑战项目将在两年内：(A)在免疫、传染病和慢性炎症性疾病方面推进自噬的整个领域，特别强调粘膜免疫和肠道炎症，以及(B)弥合关于自噬基因多态如何在人类群体中易患炎症性肠病(IBD)的特定知识空白。拟议中的关系可以而且将在两年内得到检验。在这笔赠款结束时，我们将(I)对自噬如何在与IBD相关的粘膜免疫中发挥作用有一个全新的看法，以及(Ii)关于IRGM在克罗恩病中扮演什么角色的非常具体的知识。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，而且将为安全药物雷帕霉素的再利用提供一个令人信服的案例，用于克罗恩病的临床试验。1 Singh，S.B.，Davis，A.S.，Taylor，G.A.&Dertic，V.人类IRGM诱导自噬以消除细胞内分枝杆菌。科学313,1438-1441(2006)。2 Parkes，M.等人。自噬基因IRGM和多个其他复制基因的序列变异导致克罗恩病的易感性。NAT Genet 39,830-832(2007) 与公共卫生相关：在美国，有50万人患有克罗恩病，这是一种使人虚弱的慢性肠道炎症性疾病，由于肠梗阻经常需要手术。我们一直在研究一种名为IRGM的基因，在通过基因研究将其与克罗恩病联系起来之前。我们发现，这种基因控制着一个被称为自噬的过程，这个过程可以净化我们体内所有细胞的内部，包括肠道细胞，并清除它们溃烂的细胞内细菌和炎性微生物产物。在这个项目中，我们将确定克罗恩病患者IRGM基因的突变如何影响自噬，以及这如何导致肠道炎症和进行性组织病理和破坏。我们将能够在两年的时间内通过研究克罗恩病患者的血细胞和手术切除组织，并分析IRGM在这些标本自噬中的功能来破译这一点。作为两年后的最终产品，基于通过这项工作获得的知识，医生将能够开始使用目前FDA批准的现有药物进行临床试验，以增加或减少患者的自噬，并帮助治愈那些患有克罗恩病的人。

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.