THE ROLE OF INTESTINAL EPITHELIAL BARRIER FUNCTION AND HOST DEFENSE

肠道上皮与肠道微生物区系的动态相互作用需要屏障功能与宿主防御反应的协调，以维持肠道内环境的稳定。然而，这种真核和原核生物的串扰所涉及的机制只被部分了解。为了克服肠道屏障，几种肠道病原体已经进化出不同的策略来干扰紧密连接的功能，一种专门的 肠上皮细胞最顶端的膜域，维持细胞的极性，为离子和大分子创建选择性和受调节的屏障。概述的实验将继续我们的目标，以揭示在宿主防御反应中促进肠道屏障功能维持的机制。在之前的资助期间，我们已经在肠上皮细胞的紧密连接中发现了RhoA的鸟嘌呤核苷酸交换因子--全球环境基金-H1。通过控制紧密连接的形成、病原体对细胞的侵袭和炎性宿主反应的激活，gef-h1可能是上皮细胞防御病原体的中心。定位于紧密连接的全球环境基金-H1的机制，以及负责其释放和在肠道上皮细胞中启动信号事件的机制尚不清楚。我们推测，全环基金-H1是Rho的关键调节因子 紧密连接中的GTPase依赖机制；这些机制共同决定了肠道屏障功能对共生细菌和病原菌挑战的适应。本研究的总体目标是确定全球环境基金H1在调节肠上皮屏障功能中的生物学功能，并确定负责全球环境基金H1介导的保护肠道上皮细胞免受病原体细胞入侵的分子机制。

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.