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

描述（由申请人提供）：我对研究的兴趣可以追溯到高中时，我的父亲被诊断出患有胰腺癌。缺乏对这种疾病的知识和治疗方法使我在本科时从事癌症研究。在我的MD/PhD培训期间，我的兴趣扩大到包括细胞生物学和免疫学。这些兴趣塑造了我追求内科住院医师和肿瘤学奖学金的决定。在哈佛公共卫生学院劳里·格利姆彻博士的实验室工作期间，我正在研究肠道微生物在炎症性肠病中的免疫学和作用。我的博士后培训将使我准备好领导一个研究炎症和微生物在结肠癌中的作用的实验室。 我们已经开发了一种类似于人类疾病的溃疡性结肠炎（UC）小鼠模型。先天免疫系统中T-bet的缺失导致自发性和传染性UC，在缺乏适应性免疫（称为TRUC）的情况下，并且在免疫完整的宿主中增加对结肠炎的易感性。我建议1）确定树突状细胞（DC）是否是TRUC结肠炎所必需的，以及将DC募集到TRUC结肠的因素2）探测TRUC中上皮屏障和微生物群的作用，3）确定TRUC中激活DC的细菌源性信号。 目的1将着重于T-bet和结肠DC的作用，并采用转基因方法来证明DC是TRUC中结肠炎所必需和足够的效应细胞。采用细胞生物学和微生物学的方法，我将彻底询问上皮屏障和关键，促炎微生物在这个结肠炎。使用细菌衍生的产物和小鼠模型，我将寻求确定TRUC结肠炎中激活DC的细菌衍生的信号。 相关性：炎症性肠病是一种破坏性疾病，可导致显著的发病率和死亡率。我们已经建立了一个溃疡性结肠炎的小鼠模型，它与人类疾病非常相似。对该模型的研究有望为这些疾病的患者找到新的治疗方法。

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.