ROLE OF CD98 IN INTESTINAL PERMEABILITY

描述（由申请人提供）：主要上皮通透性屏障由细胞-细胞和细胞-细胞外基质（ECM）接触触发的级联事件控制和调节。整合素调节和功能的异常与各种病理状况的病因学有关，包括炎性病症如炎性肠病。除了整联蛋白，几类细胞表面糖蛋白，包括CD 98，已被证明参与整联蛋白介导的事件。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）CD 98似乎与β 1整合素相关，破坏了由外向内的整合素信号传导，这通常赋予细胞骨架组织，屏障功能的关键要素（J Biol. Chem. 2001，276（42）：39282-9）;和ii）一种新的机制似乎整合了细胞事件，如粘附和氨基酸转运，以及细胞表面分子的直接结合，包括CD 98和ICAM-1（J Biol.Chem.2003，278（26）：23672-7）。在目前的RO 1应用程序中，我们建议探索这些现象的分子机制。因此，本提案的总体目的是更好地了解糖蛋白CD 98在肠上皮中的表达及其在调节肠上皮通透性的上皮-上皮和上皮-基质相互作用中的功能。具体目标1和2将检验CD 98是调节肠上皮通透性屏障的关键分子的假设。具体目标3和4将检查CD 98和β 1整合素簇信号分子调节Caco 2-BBE单层细胞旁途径的假设。该项目将涉及各种生物化学和生物物理方法，重点是分子方法。该提案的完成应该从分子上定义CD 98在肠道屏障通透性调节中的功能作用。

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.