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，当时我的父亲被诊断出患有胰腺癌。由于缺乏对这种疾病的了解和治疗方法，我在本科时就开始了癌症研究。在我的医学博士/博士培训期间，我的兴趣扩大到细胞生物学和免疫学。这些兴趣促使我决定获得内科住院医师资格和肿瘤学专科医师资格。在哈佛大学公共卫生学院 Laurie Glimcher 博士的实验室进行研究期间，我正在研究共生微生物在炎症性肠病中的免疫学及其作用。我的博士后培训将使我准备好领导一个研究结肠癌中炎症和微生物功能的实验室。 我们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 的缺失会导致自发性和传染性 UC，缺乏适应性免疫（称为 TRUC），并且免疫完整的宿主对结肠炎的易感性增加。我建议 1) 确定树突状细胞 (DC) 是否是 TRUC 结肠炎所必需的，以及招募 DC 到 TRUC 结肠的因素 2) 探究 TRUC 中上皮屏障和微生物群的作用，3) 确定 TRUC 中激活 DC 的细菌衍生信号。 目标 1 将重点关注 T-bet 和结肠 DC 的作用，并采用转基因方法证明 DC 是 TRUC 中结肠炎所必需和充分的效应细胞。我将采用细胞生物学和微生物学方法，彻底研究结肠炎中的上皮屏障和关键的促炎微生物。我将使用细菌衍生产品和小鼠模型来确定 TRUC 结肠炎中激活 DC 的细菌衍生信号。 相关性：炎症性肠病是毁灭性的疾病，会导致显着的发病率和死亡率。我们已经建立了一种与人类疾病非常相似的溃疡性结肠炎小鼠模型。该模型的研究有望为患有这些疾病的患者找到新的疗法。

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.