GI Nematodes and Functional Responses to Inflammation

描述：（由申请人提供）： 胃肠道有助于宿主防御， 通过刻板的功能反应， 存在细胞因子。克罗恩病和大多数结肠炎的鼠模型是 与Th 1细胞因子的过度产生有关。相比之下，主机 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对于 Th 2模式的建立和Th 1的下调 IL-4或其他2型细胞因子在体内的研究很少。 此外，IL-13与IL-4共享许多生物学活性，其通过在细胞内以一种特定的方式起作用。 共同受体链这一建议的核心前提是， 结肠炎引起的平滑肌和上皮细胞功能的变化将 通过施用外源性IL-4或IL-13，或通过上调 它们通过线虫感染的内源性生产。我们建议 细胞因子改变肠道功能的机制涉及受体介导的 Stat 6信号通路、肥大细胞和肥大细胞介质的活化，以及 肠神经有三个具体目标。1.）确定的轮廓 存在于肠道中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功能; 2.）确定改变的作用 Th 2细胞因子在结肠炎引起的上皮细胞和平滑肌细胞的改变中的作用 肌肉功能; 3.）确定上皮细胞改变的机制， 用IL-4治疗的患有和不患有结肠炎的小鼠的平滑肌功能， IL-13或线虫感染。根据我们的初步数据， 2型细胞因子对小细胞和巨噬细胞具有显著的区域特异性作用， 大肠，以及恢复1型/2型分布平衡将 对IBD中受损的分泌运动功能具有治疗益处。

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.