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

描述（由申请人提供）：申请人的职业目标是成为人类粘膜免疫学领域的独立科学家，重点研究树突状细胞（dc）在幽门螺杆菌感染中的作用。为了实现这一目标，申请人提出了一个职业发展计划，将使她获得更多的黏膜DC研究经验，并通过实践经验，正式课程工作和指导获得自身免疫研究，癌症生物学，蛋白质组学方法，拨款写作和领导技能方面的培训。一个非常有成就的调查团队将监督申请人的职业发展，并就研究项目的各个方面提供专业知识。该项目的研究部分旨在阐明dc导致幽门螺杆菌胃炎长期后遗症（即胃萎缩和瘤变）的机制。总的假设是，胃上皮细胞和潜在的固有层dc之间的串扰在人类幽门螺杆菌感染的疾病进展调节中发挥了重要作用。这一假设将通过以下具体目的进行验证：(1)确定人类胃上皮细胞是否在早期幽门螺杆菌感染中调节胃DC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抗原呈递细胞清除缺陷是否参与慢性炎症和胃自身免疫；(3)幽门螺杆菌胃炎患者胃DC分泌IL-8和MIF是否通过CXCR2-EGF-R轴促进上皮细胞增殖。特异性目的1和2将探讨在早期或慢性幽门螺杆菌感染的情况下，活的、凋亡的和坏死的上皮细胞对DC功能的影响，而特异性目的3将关注DC来源的信号对胃上皮细胞增殖的影响，从而完成串音循环。

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.