Crohn's Disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that leads to severe impairments of quality of life and substantial health care costs. The disease results from altered immune responses to intestinal bacteria and other microbes, and frequently is driven by susceptibility genes. The Immunity Related GTPase (IRG) M gene is a recently identified CD susceptibility gene. IRGM encodes a protein that regulates autophagy and mitophagy; however, how IRGM impacts CD pathogenesis is unknown. The goal of the proposed work is to establish a mouse system to model the function of IRGM function with respect to autophagy and intestinal biology. We have found that mouse Irgm1 that shares with human IRGM the ability to modulate autophagy and mitophagy. Additionally, Irgm1-deficient mice exhibit enhanced intestinal inflammation when challenged with experimental models of colitis. These and other preliminary data establish a working hypothesis: Lack of autophagic function due to Irgm1 deficiency leads to impaired functioning in different populations of immune cells that collectively contribute to enhanced intestinal inflammation. The primary goals of this proposal will be: (1) to discern the specific immune processes regulated by Irgm1 in the intestine that are key in modulating intestinal inflammation, and (2) to determine the underlying Irgm1-regulated molecular pathways that instruct those immune functions, particularly the role of autophagy and mitophagy. The following specific aims will be addressed:
Aim 1 A. Determine whether Irgm1 promotes immune responses in the intestinal epithelium important for controlling intestinal bacteria.
Aim1 B. Determine whether Irgm1 promotes immune processes in hematopoietic cells - either homeostatic or inflammatory - in response to intestinal bacteria.
Aim 1 C. Determine which Irgm1-mediated immune responses and cell types are key in suppressing excessive intestinal inflammation.
Aim 2 A. Determine whether Irgm1 promotes intestinal immune function by stimulating autophagy.
Aim 2 B. Determine whether Irgm1 promotes intestinal immune function by stimulating a type of autophagy called mitophagy. These studies will fill a major knowledge gap by modeling how an important CD susceptibility gene, IRGM, affects immune homeostasis in the intestine, potentially establishing future therapeutic targets. The studies will also increase understanding of how autophagic processes modulate intestinal immunity, a question that is broadly relevant, as a number of CD susceptibility genes and mouse models are now known to perturb autophagic responses.
Crohn's Disease (CD) and other inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract characterized by abdominal pain, diarrhea and weight loss, which lead to severe impairments of quality of life and substantial health care costs. Within the VA health system, IBD has been a substantial burden: between 1975 and 2006, there were over 100,000 hospitalizations due to IBD. Because IBD cases are often severe illnesses, those patients consume considerable health care resources including surgery, endoscopy, and expensive biological agents (e.g., infliximab, Humira, etc.) Beyond costs, current treatments are not sufficient to ameliorate the marked impacts on health. Determining the function of genes that promote the development of CD - such as IRGM, or its mouse homologue, Irgm1 - will serve as a foundation to direct the development of novel therapies for CD and other inflammatory bowel diseases.
