Role of CD98 in Intestinal Permability

描述(申请人提供)：炎症性肠病(IBD)是一种慢性消化道炎症性疾病。IBD的病因仍然知之甚少。结直肠癌是溃疡性结肠炎和克罗恩结肠炎的一种危及生命的并发症。本申请旨在扩展我们先前的研究结果，该研究表明CD98在协调肠上皮事件中发挥重要作用。这些事件包括细胞黏附/极性、氨基酸运输和分子与细胞表面的直接结合。本课题组的研究表明，CD98的表达在IBD的发病机制中起一定作用。我们的总体假设是，结肠CD98在引发和持续肠结肠炎中发挥关键作用。本研究的初步目的是探讨CD98与细菌相互作用蛋白在肠道屏障功能丧失中的作用。第二个具体目的是研究CD98在上调结肠粘膜活动中所起的作用，包括上皮细胞分化/极化，这可能反过来影响肠屏障功能。 最后，我们将探索使用有针对性的纳米技术方法下调CD98表达是否可以减少结肠炎和结肠炎相关癌症的程度。拟议的项目将使用各种生化、分子、纳米技术、体外和体内技术。我们期望通过控制CD98在结肠中的表达来开发治疗策略，以减少结肠炎和抑制结肠炎相关癌症的发展。在美国，有100多万成年人和儿童患有IBD及其并发症，如结肠炎相关癌症。基于对IBD发病机制的更好理解，新的治疗策略将改善此类患者的临床护理。

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the digestive tract. The etiology of IBD remains poorly understood. Colorectal cancer is a life-threatening complication of both ulcerative and Crohn's colitis. The present application seeks to extend the findings of our previous studies, which showed that CD98 plays an important role in coordination of intestinal epithelial events. Such events include cell adhesion/polarity, amino acid transport, and direct binding of molecules to cell surfaces. Studies by our group have shown that CD98 expression plays a role in the pathogenesis of IBD. Our overall hypothesis is that colonic CD98 plays a critical role in initiating and perpetuating intestinal colitis. The initial aim of this proposal is to investigate the role played by interactin of CD98 with bacteria in terms of the loss of intestinal barrier function. The second specific aim is to investigate the role played by CD98 in upregulation of colonic mucosal activities including epithelial cell differentiation/polarization that may, in turn, affect intestinal barrier function. Finally, we will explore whether knockdown of CD98 expression, using a targeted nanotechnological approach, reduces the extent of colitis and colitis-associated cancer. The proposed project will use a variety of biochemical, molecular, nanotechnological, ex vivo, and in vivo techniques. We expect that we will develop therapeutic strategies, based on manipulation of CD98 expression in the colon, to reduce colitis and to inhibit development of colitis-associated cancer. More than one million adults and children in the United States suffer from IBD and complications of the condition, such as colitis-associated cancer. New therapeutic strategies based on a better understanding of IBD pathogenesis will improve the clinical care of such patients.