Inflammatory bowel disease (IBD) affects over 1 million Americans. Although in many circumstances medications have allowed us to gain control of disease, IBD still results in significant morbidity and mortality. One important genetic pathway identified in IBD is activated by a molecule called interleukin(IL)-23. Recently, a new type of lymphocyte, called an innate lymphoid cell (ILC), was discovered that responds to IL-23.
The aim of this proposal is to support my additional research training to characterize the function and regulation of ILCs in IBD and help me transition to an independent research career focused on microbial regulation of immune cells in IBD. Dr. Dan Littman, an expert in the microbial regulation of intestinal immune cell activation, and Dr. Timothy Wang, an expert in microbial-dependent intestinal inflammation, will serve as co-mentors of this proposal. First, genetic material (i.e. RNA) from ILCs isolated from the intestines of patients with IBD (or non- IBD) donors will be defined using state-of-the-art sequencing technology. I will participate in formal training in sequence analysis in order to analyze this data and define genes/genetic pathways activated in intestinal ILCs of patients with IBD. The second main aspect of my proposal is to define the interaction of these intestinal ILCs with dendritic cells (DCs), specialized immune cells that capture proteins at sites of inflammation and present the processed protein to T cells to stimulate an immune response. Several types of DCs exist within the mouse intestine with different capacity to capture proteins and/or stimulate T cells. In order to investigate their interaction with ILCs, I will use novel mouse models generated in our lab that allow me to track particular DC subsets with a fluorescent label and to ablate specific DC subsets in a live mouse. Furthermore, I will characterize the DC subsets present in the human colon and evaluate their ability to interact with human intestinal ILCs in culture. Finally, this work will use """"""""germ-free"""""""" mice to test the ability of particular bacteria from IBD and non-IBD donors to support ILC activity in mouse models of colitis. In order to provide scientific feedback and career development advice, I have assembled an Advisory Committee including Dr. Lloyd Mayer, an expert in IBD immunology;Dr. Megan Sykes, an expert in human immunology;Dr. Martin Blaser, an expert in intestinal microbiology;and Dr.
J aim e Rubin, an expert in scientific research career development. With this scientific and career development plan, I believe this proposal will offer new insight into disease pathogenesis as well as diagnostic and therapeutic strategies for IBD and serve as a strong foundation for my transition to an independent research career.
Inflammatory bowel disease (IBD) affects over 1 million Americans, resulting in significant morbidity and mortality. Recently, a new type of lymphocyte, called an innate lymphoid cell (ILC), was discovered that promotes intestinal healing-a crucial clinical endpoint in IBD-and the function of these cells is regulated by interleukin-23-a signaling pathway linked to IBD. Thus, the aim of this proposal is to characterize the function and regulation of ILCs in IBD in order to provide new insight into disease pathogenesis as well as diagnostic and therapeutic strategies for IBD.
|Longman, Randy S; Littman, Dan R (2015) The functional impact of the intestinal microbiome on mucosal immunity and systemic autoimmunity. Curr Opin Rheumatol 27:381-7|
|Longman, Randy S; Diehl, Gretchen E; Victorio, Daniel A et al. (2014) CXâ‚ƒCR1âº mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J Exp Med 211:1571-83|
|Longman, Randy S; Yang, Yi; Diehl, Gretchen E et al. (2013) Microbiota: host interactions in mucosal homeostasis and systemic autoimmunity. Cold Spring Harb Symp Quant Biol 78:193-201|