Disease Initation and the role of DCs in the TRUC Model of ulcerative colitis

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): My interest in research dates back to high school when my father was diagnosed with pancreatic cancer. Lack of knowledge about and treatments for this disease led me to cancer research as an undergraduate. During my MD/PhD training, my interests broadened to encompass cell biology and immunology. These interests shaped my decision to pursue a residency in internal medicine and fellowship in oncology. During my fellowship in Dr. Laurie Glimcher's laboratory at the Harvard School of Public Health, I am studying the immunology of and role of commensal microbes in inflammatory bowel disease. My post-doctoral training will prepare me to direct a laboratory that studies the function of inflammation and microbes in colon cancer. We have developed a mouse model of ulcerative colitis (UC) that resembles the human disease. Loss of T-bet in the innate immune system results in spontaneous and communicable UC, in the absence of adaptive immunity (termed TRUC) and increased susceptibility to colitis in immunologically intact hosts. I propose to 1 ) determine whether dendritic cells (DCs) are necessary for TRUC colitis and the factors recruiting DCs to TRUC colons 2) probe the role of the epithelial barrier and the microbiota in TRUC and 3) determine the bacterial-derived signals activating DCs in TRUC. Aim 1 will focus on the role of T-bet and colonic DCs and employs transgenic approaches to prove that the DC is the effector cell necessary and sufficient for colitis in TRUC. Employing both cell biological and microbiological approaches, I will thoroughly interrogate the epithelial barrier and key, pro-inflammatory microbes in this colitis. Using both bacterial derived products and mouse models, I will seek to determine the bacterial derived signals activating DCs in TRUC colitis. RELEVANCE: Inflammatory bowel diseases are devastating illnesses that cause significant morbidity and mortality. We have generated a mouse model of ulcerative colitis that bears a great resemblance to the human disease. Studies of this model will hopefully lead to the identification of new therapies for patients with these diseases.