GI Nematodes and Functional Responses to Inflammation

描述：(申请人提供)： 建议的研究是胃肠道对宿主防御的贡献 通过配置文件编排的刻板印象的功能响应 细胞因子的存在。克罗恩病和大多数小鼠结肠炎模型 与Th1细胞因子的夸大产生有关。相比之下，东道主 对肠道线虫感染的防御主要依赖于2型 细胞因子IL-4和IL-13。在2型细胞因子中，IL-4是最重要的 Th2细胞亚群的建立及Th1细胞的下调 然而，关于IL-4或其他2型细胞因子的体内研究很少。 此外，IL-13与IL-4有许多共同的生物学活性，它们是通过作用于 共同的受体链。这项提议的中心前提是 结肠炎引起的平滑肌和上皮细胞功能的变化将 通过注射外源性IL-4或IL-L3或通过上调表达而改善 它们通过线虫感染产生的内源产物。我们建议， 细胞因子改变肠道功能的机制涉及受体介导 激活Stat6信号通路、肥大细胞和肥大细胞介体，以及 肠神经。有三个具体目标。1)确定的配置文件 肠道中存在的细胞因子控制上皮细胞和平滑肌 在结肠炎和线虫感染中的作用；确定更改的角色 Th2细胞因子在结肠炎引起的上皮细胞和平滑肌细胞改变中的作用 肌肉功能；3.)确定上皮细胞改变的机制和 IL-4对结肠炎小鼠和非结肠炎小鼠血管功能的影响 IL-13，或线虫感染。根据我们的初步数据，我们预计 2型细胞因子对小细胞和小细胞有显著的区域特异性作用 大肠，以及恢复类型1/类型2轮廓平衡将 对IBD患者的分泌运动功能受损有治疗作用。

DESCRIPTION: (provided by the applicant): The overall hypothesis of the proposed studies is that the gastrointestinal tract contributes to host defense through stereotypic functional responses that are orchestrated by the profile of cytokines present. Crohn's disease and most murine models of colitis are linked to exaggerated production of Th1 cytokines. In contrast, the host defense to enteric nematode infection is dependent primarily on the type 2 cytokines, IL-4 and IL- 13. Of the type 2 cytokines, IL-4 is most important for the establishment of the Th2 profile and for the down regulation of Th1 pathway, yet there are few studies of IL-4, or other type 2 cytokines, in vivo. In addition, IL-13 shares many biological activities with IL-4 by acting at a common receptor chain. The central premise of this proposal is that colitis-induced changes in the smooth muscle and epithelial cell function will be improved by administration of exogenous IL-4 or IL-l3, or by up-regulation of their endogenous production via nematode infection. We propose that the mechanism by which cytokines alter gut function involves receptor-mediated activation of Stat6 signaling pathways, mast cells and mast cell mediators, and enteric nerves. There are 3 specific aims. 1.) Determine that the profile of cytokines present in the gut controls epithelial cell and smooth muscle function in colitis and nematode infection; 2.) Determine the role of altered Th2 cytokines in colitis-induced alterations in epithelial cell and smooth muscle function; 3.) Determine the mechanisms of altered epithelial cell and smooth muscle function in mice with and without colitis and treated with IL-4, IL-13, or nematode infection. Based on our preliminary data, we expect that type 2 cytokines have significant region-specific actions on the small and large bowel, and that restoration of the balance of type 1/type 2 profiles will be of therapeutic benefit to the impaired secretomotor function in IBD.