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

我对研究的兴趣可以追溯到高中，当时我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。期间 我在哈佛公共卫生学院劳里·格利姆彻博士的实验室工作，研究 肠道微生物在炎症性肠病中作用及免疫学我的博士后培训将 让我准备好领导一个实验室，研究炎症和微生物在结肠癌中的作用。 我们已经开发了一种类似于人类疾病的溃疡性结肠炎（DC）小鼠模型。损失 先天性免疫系统中的T-bet导致自发性和传染性UC，在缺乏T-bet的情况下， 适应性免疫（称为TRUC）和免疫完整宿主对结肠炎的易感性增加。我 建议1）确定先天免疫系统如何在结肠炎症的发展中起作用， 2)询问微生物群落的复杂性，以及3）了解T-bet和 其他基因调节宿主-植物关系。目的1：探讨T-bet和结肠DCs的作用 并采用转基因方法证明DC是结肠炎的效应细胞来源， 在TRUC。采用免疫学和生物化学方法，我将研究细胞因子环境及其作用 TRUC模型中的转录调节因子。在目标2中，1将使用以下方法确定驱动结肠炎的微生物： 分析TRUC和基因型对照产生的16 S rDNA计数。我会用分子 生物学和微生物学的方法来验证我的发现。在目标3中，我将使用TRUC中的应变差异 使用全基因扫描、分子生物学和细胞来识别结肠炎的易感性修饰基因 生物学方法 炎症性肠病是导致显著发病率和死亡率的毁灭性疾病。我们 已经建立了一个溃疡性结肠炎的小鼠模型，该模型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。

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 (DC) 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 how the innate immune system functions in the development of colonic inflammation, 2)interrogate the complex nature of commensal microbial communities, and 3) understand how T-bet and other genes moderate host-commensal relationships. Aim 1will focus on the role of T-bet and colonic DCs and employs transgenic approaches to prove that the DC is the effector cell necesary and sufficient for colitis in TRUC. Employing both immunologic and biochemical approaches, I will study the cytokine milieu and its transcriptional regulators in the TRUC model. In Aim 2,1 will determine the microbes driving colitis using analysis of 16S rDNA enumerations generated from TRUC and genotype controls. I will use both molecular biology and microbiology approaches to validate my findings. In Aim 3, I will use strain differences in TRUC to identify susceptibility modifying genes in colitis using gene wide scanning, molecular biology, and cell biology methodologies. 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.