Role of CD98 in Intestinal Permeability

描述（由申请人提供）：炎症性肠病（IBD）是一种消化道慢性炎症。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之前的研究结果，这些研究表明CD98在肠上皮事件的协调中起重要作用。这些事件包括细胞粘附/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的发病机制中起作用。我们的总体假设是结肠CD98在引发和持续肠结肠炎中起关键作用。本提案的最初目的是研究CD98与细菌相互作用在肠屏障功能丧失方面所起的作用。第二个具体目的是研究CD98在结肠粘膜活动上调中所起的作用，包括上皮细胞分化/极化，这可能反过来影响肠屏障功能。

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.