ROLE OF CD98 IN INTESTINAL PERMEABILITY

描述(申请人提供)：主要的上皮通透性屏障由细胞-细胞和细胞-细胞外基质(ECM)接触触发的一系列事件控制和调节。整合素调节和功能的异常与各种病理情况的病因有关，包括炎症性肠病等炎症性疾病。除了整合素，包括CD98在内的几类细胞表面糖蛋白已被证明参与了整合素介导的活动。通过我的CCFA研究奖资助的研究，我们已经证明了以下几点：i)CD98似乎与β1整合素相关，扰乱了通常赋予细胞骨架组织的由外而内的整合素信号，这是屏障功能的关键要素(J Biol)。化学。以及ii)一种新的机制似乎整合了细胞事件，如黏附和氨基酸运输，以及细胞表面分子的直接结合，包括CD98和ICAM-1(J Biol)。化学。2003年，278(26)：23672-7)。在目前的RO1应用中，我们建议探索这些现象的分子机制。因此，这项建议的总体目的是为了更好地了解糖蛋白CD98在肠上皮细胞中的表达及其在调节肠上皮通透性的上皮-上皮和上皮-基质相互作用中的作用。特定目标1和2将检验CD98是调节肠上皮通透性屏障的关键分子的假设。特定的AIMS 3和4将检验CD98和Beta1整合素簇信号分子的假说，该信号分子调节CACO2-BBE单层中的旁细胞途径。该项目将涉及各种生化和生物物理方法，重点是分子方法。该提案的完成将从分子上确定CD98在调节肠道屏障通透性中的功能作用。

DESCRIPTION (provided by applicant): The major epithelial permeability barriers are controlled and regulated by a cascade of events that is triggered by cell-cell and cell-extracellular matrix (ECM) contacts. Anomalies of integrin regulation and function have been implicated in the etiology of various pathologic conditions, including inflammatory disorders such as inflammatory bowel disease. In addition to integrins, several classes of cell surface glycoproteins, including CD98, have been shown to participate in integrin-mediated events. Through research funded by my CCFA research award, we have demonstrated the following: i) CD98 appears to associate with beta 1 integrin, disrupting outside-in integrin signaling, which normally confers cytoskeletal organization, a critical element of barrier function (J Biol. Chem. 2001, 276(42):39282-9); and ii) a novel mechanism appears to integrate cellular events, such as adhesion and amino acid transport, and the direct binding of cell surface molecules, including CD98 and ICAM-1 (J Biol. Chem. 2003, 278(26):23672-7). In the present RO1 application we propose to explore the molecular mechanisms of these phenomena. Thus, the general aim of this proposal is to better understand the expression of glycoprotein CD98 in the intestinal epithelium and its function in the epithelial-epithelial and epithelial-matrix interactions that regulate intestinal epithelial permeability. Specific aims 1 and 2 will examine the hypothesis that CD98 is a key molecule in the regulation of intestinal epithelial permeability barriers. Specific aims 3 and 4 will examine the hypothesis CD98 and beta1 integrin cluster signaling molecules that regulate the paracellular pathway in Caco2-BBE monolayers. The project will involve a variety of biochemical and biophysical methods with an emphasis on molecular approaches. The completion of the proposal should molecularly define the functional role of CD98 in the regulation of the intestinal barrier permeability.