gd IEL migration and epithelial interactions in intestinal disease

肠道疾病中的 gd IEL 迁移和上皮相互作用

基本信息

批准号：
8423799
负责人：
Karen Leigh Edelblum
金额：
$ 14.7万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8423799
关键词：
Achievement Advisory Committees Affect Autoimmune Diseases Basement membrane Behavior Biology Celiac Disease Cell Communication Cell membrane Cellular biology Chicago Chronic Colitis Confocal Microscopy Data Development Development Plans Disease Disease model Elements Environment Epithelial Epithelial Cells Epithelium Exhibits Extracellular Space Foundations Future Gastrointestinal Diseases Goals Health Homeostasis Human Immigration Immune Immune System Diseases Immunology In Vitro Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Injury Interleukin-15 Intestinal Diseases Intestinal Mucosa Intestines Investigation Lateral Lead Lymphocyte Lymphocyte Function Maintenance Mediating Mentors Modeling Molecular Molecular Biology Molecular Immunology Mus Parasites Pathogenesis Proteins Regulation Research Research Personnel Role Surface T-Lymphocyte Techniques Tight Junctions Time Training Universities career career development cell motility cell type cytokine design graft vs host disease improved in vivo insight interdisciplinary approach intestinal epithelium intestinal homeostasis intraepithelial migration monolayer novel therapeutic intervention occludin prevent research and development response response to injury

项目摘要

DESCRIPTION (provided by applicant): 34 intraepithelial lymphocytes (IELs) are located within the intestinal epithelial monolayer, either in contact with the epithelial basal surface along the basement membrane, or in the lateral intercellular space between epithelial cells and below the tight junction. 34 IELs have been shown to prevent or exacerbate intestinal disease depending on the context, but 34 IEL behavior and interactions with other cell types in the intestinal mucosa are largely undefined. Until now, 34 IELs were presumed to be sessile, yet my preliminary data demonstrate that 34 IELs exhibit dynamic migratory behavior resulting in extensive interactions with the epithelium. Furthermore, I have shown that 34 IEL motility is dependent upon epithelial and 34 IEL expression of the tight junction protein occludin, and that certain cytokines alter this dynamic migratory behavior both in vitro and in vivo. Together, these observations have led to the central hypothesis that disruption of mucosal homeostasis adversely affects occludin-dependent 34 IEL migration leading to the exacerbation of disease. The aims of this application are to 1) elucidate the molecular mechanisms by which 34 IELs and epithelial cells interact during 34 IEL migration, 2) determine the effect of 34 IEL migration in IL-15 mediated small intestinal disease and 3) determine how 34 IEL migration contributes to the protection or exacerbation of colitis. A combination of in vivo confocal microscopy, traditional mucosal immunology, and epithelial cell biology techniques will be used to provide new mechanistic insights into the contribution of 34 IEL migration and subsequent epithelial interactions during disease. Moreover, these studies will enhance our understanding of how 34 IELs function within the mucosal microenvironment to regulate health and disease development, and may ultimately lead to new therapeutic approaches designed to modulate 34 IEL motility as means to treat intestinal inflammation. These studies are the first step toward achievement of my long-term goal to identify epithelial/immune cell interactions and determine the relevance of these interactions to IBD and celiac disease. The proposed research and career development plan, along with my mentors, advisory committee and the interdisciplinary approaches encouraged at the University of Chicago, will provide the support and additional training necessary to become an independent investigator in an academic research environment.

描述（由申请人提供）：34个上皮内淋巴细胞（IEL）位于肠上皮单层内，或者沿着基底膜与上皮基底表面接触，或者位于上皮细胞之间和紧密连接下方的横向细胞间隙中。 34 IEL 已被证明可以根据具体情况预防或加剧肠道疾病，但 34 IEL 的行为以及与肠粘膜其他细胞类型的相互作用在很大程度上尚不清楚。到目前为止，34 个 IEL 被认为是无柄的，但我的初步数据表明，34 个 IEL 表现出动态迁移行为，导致与上皮细胞发生广泛的相互作用。此外，我已经证明 34 IEL 运动取决于紧密连接蛋白 occludin 的上皮和 34 IEL 表达，并且某些细胞因子在体外和体内都会改变这种动态迁移行为。总之，这些观察结果得出了一个中心假设：粘膜稳态的破坏会对依赖于 occludin 的 34 IEL 迁移产生不利影响，从而导致疾病恶化。本申请的目的是 1) 阐明 34 IEL 和上皮细胞在 34 IEL 迁移过程中相互作用的分子机制，2) 确定 34 IEL 迁移在 IL-15 介导的小肠疾病中的作用，以及 3) 确定 34 IEL 如何迁移有助于保护或加剧结肠炎。体内共聚焦显微镜、传统粘膜免疫学和上皮细胞生物学技术的结合将用于为疾病期间 34 IEL 迁移和随后的上皮相互作用的贡献提供新的机制见解。此外，这些研究将增强我们对 34 IEL 如何在粘膜微环境中发挥作用以调节健康和疾病发展的理解，并可能最终产生旨在调节 34 IEL 运动性作为治疗肠道炎症的新治疗方法。这些研究是实现我的长期目标的第一步，即确定上皮/免疫细胞相互作用并确定这些相互作用与 IBD 和乳糜泻的相关性。拟议的研究和职业发展计划，以及我的导师、咨询委员会和芝加哥大学鼓励的跨学科方法，将为成为学术研究环境中的独立研究者提供必要的支持和额外培训。