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

描述(申请人提供)：我对研究的兴趣可以追溯到高中，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知识和治疗方法，我在本科时就开始了癌症研究。在我的医学博士培训期间，我的兴趣扩大到细胞生物学和免疫学。这些兴趣决定了我选择内科住院医师和肿瘤学研究员。在哈佛大学公共卫生学院Laurie Glimcher博士的实验室工作期间，我正在研究共生微生物在炎症性肠病中的免疫学和作用。我的博士后培训将为我领导一个实验室做好准备，该实验室研究结肠癌中炎症和微生物的功能。 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的丢失会导致自发的和传染性的UC，在免疫功能正常的宿主中缺乏获得性免疫(称为TRUC)，并增加结肠炎的易感性。我建议1)确定树突状细胞(DC)是否是Truc结肠炎所必需的，以及招募DC进入Truc结肠的因素；2)探讨上皮屏障和微生物区系在Truc中的作用；3)确定细菌来源的信号激活Truc中的DC。目的1将重点放在T-bet和结肠树突状细胞的作用上，并利用转基因方法证明DC是结肠炎发生的必要条件和充分条件。利用细胞生物学和微生物学的方法，我将彻底询问结肠炎中的上皮屏障和关键的促炎微生物。使用细菌衍生产品和小鼠模型，我将寻求确定在真性结肠炎中激活DC的细菌衍生信号。 相关性：炎症性肠病是一种破坏性疾病，会导致严重的发病率和死亡率。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。对这一模式的研究有望为这些疾病的患者确定新的治疗方法。

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.