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H.幽门感染为了实现这一目标，申请人提出了一个职业发展计划，这将使她能够通过实践经验，正式的课程工作和指导，获得粘膜DC研究的额外经验以及自身免疫研究，癌症生物学，蛋白质组学方法，赠款写作和领导技能的培训。一个非常有成就的调查团队将监督申请人的职业发展，并提供研究项目各个方面的专业知识。 本项目的研究部分旨在阐明DCs对H.幽门胃炎，即，胃萎缩和肿瘤。总的假设是胃上皮细胞和下层固有层DC之间的相互作用对人类H.幽门感染这一假设将通过以下具体目的进行检验：（1）确定在H早期，人胃上皮细胞是否调节胃DC活化和DC功能，包括DC诱导的T细胞增殖。pylori感染;（2）确定H. pylori胃炎促进慢性炎症和胃自身免疫;（3）确定胃DC分泌IL-8和MIF是否通过H.幽门胃炎具体目标1和2将解决在早期或慢性H的背景下，活的、凋亡的和坏死的上皮细胞对DC功能的影响。pylori感染，而特异性目标3将集中于DC衍生的信号对胃上皮细胞增殖的影响，从而完成了串扰循环。 我们预期，DC和上皮细胞在慢性H。幽门螺杆菌感染引起相互激活，导致非消退性炎症和上皮细胞更新的失调，这是慢性幽门螺杆菌进展的关键因素。幽门炎到胃腺癌。这个项目将大大提高我们对人类慢性疾病机制的理解。幽门螺杆菌感染，也将为Bimczok博士作为一个独立的科学家的发展提供关键的培训。

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.