Dendritic Cell-Epithelial Cell Crosstalk in Human H. pylori Gastritis

申请人的职业目标是成为人类黏膜免疫学领域的一名独立科学家，专注于树突状细胞(DC)在幽门螺杆菌感染中的作用。为了实现这一目标，申请者提出了一项职业发展计划，允许她通过实践经验、正规课程工作和指导，获得更多的粘膜DC研究经验，以及自身免疫研究、癌症生物学、蛋白质组学方法、赠款撰写和领导技能方面的培训。一支高水平的研究团队将监督申请人的职业发展，并就研究项目的个别方面提供专业知识。本项目的研究部分旨在阐明DC对幽门螺杆菌胃炎的长期后遗症，即胃萎缩和肿瘤的作用机制。总体假设是胃上皮细胞和固有层树突状细胞之间的相互作用对幽门螺杆菌感染的疾病进展起着重要的调节作用。这一假说将被验证具有下列特定目的：(1)确定在幽门螺杆菌感染早期，人胃上皮细胞是否调节胃DC的激活和DC功能，包括DC诱导的T细胞增殖；(2)确定幽门螺杆菌胃炎中凋亡上皮细胞的抗原提呈细胞清除缺陷是否有助于慢性炎症和胃自身免疫；以及(3)确定幽门螺杆菌胃炎中胃DC分泌IL-8和MIF是否通过CXCR2-EGF-R轴促进上皮细胞增殖。特定目标1和2将讨论在幽门螺杆菌早期或慢性感染的背景下，活的、凋亡的和坏死的上皮细胞对DC功能的影响，而特定目标3将集中于DC衍生信号对胃上皮细胞增殖的影响，从而完成串扰循环。 我们推测，慢性幽门螺杆菌感染中的DC和上皮细胞相互激活，导致炎症无法消退和上皮细胞代谢紊乱，这是慢性幽门螺杆菌炎症进展为胃腺癌的关键因素。该项目将极大地提高我们对人类幽门螺杆菌感染的慢性疾病机制的理解，也将为Bimczok博士作为一名独立科学家的发展提供重要的培训。

DESCRIPTION (provided by applicant): The applicant's career goal is to become an independent scientist in the field of human mucosal immunology with a focus on the role of dendritic cells (DCs) in H. pylori infection. To meet this goal, the applicant proposes a career development plan that will allow her to gain additional experience in mucosal DC research plus training in autoimmunity research, cancer biology, proteomics methods, grant writing and leadership skills through practical experience, formal course work and mentoring. A highly accomplished team of investigators will oversee the applicant's career development and provide expertise on individual aspects of the research project. The research component of this project seeks to elucidate mechanisms by which DCs contribute to the long-term sequelae of H. pylori gastritis, i.e., gastric atrophy and neoplasia. The overall hypothesis is that cross-talk between gastric epithelial cells and underlying lamina propria DCs contributes profoundly to the regulation of disease progression in human H. pylori infection. This hypothesis will be tested with the following Specific Aims: (1) Determine whether human gastric epithelial cells regulate gastric DC activation and DC function, including DC-induced T cell proliferation, in early H. pylori infection; (2) Determine whether defective antigen-presenting cell clearance of apoptotic epithelial cells in H. pylori gastritis contributes to chronic inflammation and gastric autoimmunit; and (3) Determine whether gastric DC secretion of IL-8 and MIF promotes epithelial cell proliferation through the CXCR2-EGF-R axis in H. pylori gastritis. Specific Aims 1 and 2 will address the effects of live, apoptotic and necrotic epithelial cells on DC function in the context f early or chronic H. pylori infection, whereas Specific Aim 3 will focus on the effects of DC-derived signals on gastric epithelial cell proliferation, thereby completing the cross-talk circle. We anticipate that DCs and epithelial cells in chronic H. pylori infection cause mutual activation leading to non-resolving inflammation and dysregulation of epithelial cell turnover, a key element in the progression of chronic H. pylori inflammation to gastric adenocarcinoma. This project will greatly enhance our understanding of chronic disease mechanisms in human H. pylori infection and will also provide critical training for Dr. Bimczok's development as an independent scientist.