Inflammatory bowel disease (IBD), a chronic disease of the gastrointestinal tract, is a complex disease with heterogeneous underlying genetics and symptoms. Research in the last decade has identified over 100 genes linked to an increased risk for developing IBD. Genome wide association studies have identified a single nucleotide polymorphism (SNP) associated with an increased risk of Crohn's disease, a subset of IBD, in a gene called autophagy-related 16-like 1 (ATG16L1). This gene functions in a process called autophagy, a process by which cells recycle their intracellular components when nutrients are scarce. This proposal will address the effect of a small change, or polymorphism, in this gene (ATG16L1T300A) and will focus on a cell type crucial for immune system regulation, called regulatory T cells (Treg cells). Since IBD is a disease of the gastrointestinal tract, this proposa focuses on how this gene alteration affects the generation and function of gut Treg cells. To elucidate the role of the polymorphism ATG16L1T300A in gut Treg cells, we will employ a unique mouse model in which mice harbor the same genetic mutation as people with IBD. Special mouse models that harbor fluorescent Treg cells will also be used to aid in the identification and manipulation of gut Treg cells in vitro. With these mouse models, gut Treg cells will be studied using many techniques and methods to understand how ATG16L1T300A affects Treg cell function in Aim 1. Some of the methods utilized will include: flow cytometry, ELISA, RTqPCR, and mouse models of colitis. We will use additional mouse strains in Aim 2 that have very specific receptors on their T cells, e.g. the OT-II T cell transgenic system. This system will enable us to address how autophagy affects the ability of immune cells called antigen presenting cells, to process antigen for T cell recognition. These cells are very important as they guide the development and function of Treg cells. By using two mouse models of colitis, and looking specifically at Treg cells in the intestine, Aim 3 will develop a mechanistic understanding of how the IBD-risk associated gene change ATG16L1T300A contributes to the pathophysiology of IBD. Data generated from this proposal will provide novel insight into the function of Treg cells in Crohn's disease patients homozygous for ATG16L1T300A and will be clinically relevant to the advancement of IBD precision medicine and Treg cell-based therapies. The research training plan developed for this Ruth L. Kirschstein National Research Service Award will develop my communication and writing skills and prepare me for a career as an independent researcher in the field of mucosal immunology.
Inflammatory bowel disease (IBD) afflicts over 1.4 million people in the United States. Research has linked small changes in select genes to an increased risk of developing IBD. I aim to understand how one such small gene change alters a subset of immune cells that help regulate the entire gut immune system.
| Howitt, Michael R; Lavoie, Sydney; Michaud, Monia et al. (2016) Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351:1329-33 |
