THE ROLE OF INTESTINAL EPITHELIAL BARRIER FUNCTION AND HOST DEFENSE

肠上皮屏障功能和宿主防御的作用

• 批准号: 7487453
• 负责人: HANS-CHRISTIAN REINECKER
• 金额: $ 55.99万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487453
• 关键词: Acute; Apical; Binding; Biological Models; Biological Process; Cell Differentiation process; Cell Polarity; Cells; Collaborations; Complement Factor H; Complex; Cytoskeletal Modeling; DNA Sequence Rearrangement; Disruption; Electrical Resistance; Epithelial; Epithelial Cells; Epithelium; Event; Funding; Gene Expression; Gene Silencing; Goals; Guanine Nucleotide Exchange Factors; Homeostasis; Host Defense; Immune response; In Vitro; Infection; Inflammatory; Intercellular Junctions; Intestines; Ions; Light; Localized; Maintenance; Mediating; Mediator of activation protein; Membrane; Modification; Molecular; Pathway interactions; Permeability; Proteins; Regulation; Research Personnel; Role; Salmonella; Salmonella typhimurium; Signal Pathway; Signal Transduction; Small Interfering RNA; Tight Junctions; Time; base; defense response; enteric pathogen; in vivo; insight; intestinal epithelium; macromolecule; microbial; pathogen; pathogenic bacteria; polarized cell; programs; research study; response; rho GTP-Binding Proteins; solute

The dynamic interactions of the intestinal epithelium with the intestinal microbiota require the co-ordination of the barrier function with host defense responses to maintain intestinal homeostasis. However, the mechanisms involved in this eukaryotic and prokaryotic cross-talk are only partially understood. To overcome the intestinal barrier, several enteric pathogens have evolved distinct strategies to interfere with the function of tight junctions, a specialized membrane domain at the most apical region of intestinal epithelial cells that maintains the cellular polarity and creates a selective and regulated barrier for ions and macromolecules. The outlined experiments will continue our goal to unravel the mechanisms, which facilitate the maintenance of the intestinal barrier function during host defense responses. During the previous funding period, we have identified a guanine nucleotide exchange factor for RhoA, GEF-H1, in tight junctions of intestinal epithelial cells. GEF-H1 may be central to epithelial cell defenses to pathogens by controlling the formation of tight junctions, cell invasion by pathogens, and activation of inflammatory host responses. The mechanisms, which localize GEF-H1 in tight junctions, and those responsible for its release and initiation of signaling events in intestinal epithelial cells are unknown. We hypothesize that GEF-H1 is a key regulator of Rho GTPase dependent mechanisms in tight junctions; which together, determine the adaptation of the intestinal barrier function to challenges by commensal and pathogenic bacteria. The overall goals of this proposal are to characterize the biological functions of GEF-H1 in the regulation of the intestinal epithelial barrier function and to define the molecular mechanisms, which are responsible for GEF-H1 mediated protection from pathogen cell invasion.

肠上皮与肠道菌群的动态相互作用需要屏障功能与宿主防御反应的协调，以维持肠道稳态。但是，这种真核和原核盘问中涉及的机制仅部分理解。为了克服肠屏障，几种肠道病原体已经发展出不同的策略，以干扰紧密连接的功能，这是一种专业的 肠上皮细胞最根尖的膜结构域，该区域维持细胞极性，并为离子和大分子产生选择性和调节的屏障。概述的实验将继续我们的目标揭示机制，从而有助于在宿主防御反应期间维持肠道屏障功能。在上一个资金期间，我们已经在肠上皮细胞的紧密连接处确定了RhoA的GEF-H1的鸟嘌呤核苷酸交换因子。 GEF-H1通过控制紧密连接的形成，病原体的细胞侵袭以及炎症宿主反应的激活，可能是对病原体上皮细胞防御的核心。该机制将GEF-H1定位在紧密的连接中，以及负责释放和在肠上皮细胞中发起信号事件的机制尚不清楚。我们假设GEF-H1是Rho的关键调节器 紧密连接处的GTPase依赖机制；共同确定肠道屏障功能对共生和致病细菌挑战的适应。该提案的总体目标是表征GEF-H1在调节肠上皮屏障功能中的生物学功能，并定义分子机制，这些机制负责GEF-H1介导的病原体细胞侵袭。