INTEGRINS IN KIDNEY MORPHOGENESIS

描述：（改编自申请人的摘要）-整联蛋白和 层粘连蛋白对于肾小管上皮的形态发生至关重要。 在发育过程中，整合素与层粘连蛋白和其他 细胞外基质蛋白是上皮-间充质 早期上皮的相互作用、极化和 沿着肾单位沿着单个细胞类型。 在成人中，整合素锚 细胞到基底层由不同的层粘连蛋白同种型组成。 这些相互作用的破坏以及整合素的去极化 是急性肾衰竭和其他疾病发病机制中的重要步骤。 疾病过程。 随着肾小管上皮细胞的再生，整合素和 层粘连蛋白无疑是随后再分化的主要因素。 在 在项目的这一部分，研究人员建议继续研究 整合素和细胞外基质蛋白在肾脏中的作用 形态发生 特别地，实验被设计为增加 理解整合素在损伤、再生和 在分子水平上促进肾小管上皮细胞的分化。 在具体目标1中，检查整合素的调节 肾细胞系中的配体结合活性、表达和分布 将进行ATP耗竭。 此外，基底外侧 整合素中的靶向信号将被鉴定，并且整合素的分布将被确定。 缺血大鼠肾脏中的整合素α和β亚单位将被 考察 在Specific Aim 2中，Forssman抗原在层粘连蛋白粘附、细胞粘附和细胞凋亡中的作用。 极化和形态发生将通过重建进行检查 研究、生物测定和反义方法。 的表达 肾细胞系在肾小管囊肿形成期间和之后的层粘连蛋白同种型 机械损伤，并在缺血后大鼠肾脏也将 测定 最后，整合素和层粘连蛋白在上皮细胞中的参与， 细胞极化将通过表达反义和 显性否定结构

DESCRIPTION: (Adapted from the applicant's abstract) - Integrins and laminin are crucial for morphogenesis of the kidney tubular epithelium. During development, integrins interacting with laminin and other extracellular matrix proteins are essential for epithelial-mesenchymal interactions, polarization of the early epithelium, and differentiation of individual cell types along the nephron. In the adult, integrins anchor cells to the basal lamina composed of different laminin isotypes. Disruption of these interactions together with depolarization of integrins are important steps in the pathogenesis of acute renal failure and other disease processes. As the tubular epithelium regenerates, integrins and laminin are undoubtedly major factors in the ensuing redifferentiation. In this part of the project, the investigators propose to continue studies on the roles of integrins and extracellular matrix proteins in kidney morphogenesis. In particular, experiments are designed to increase an understanding of integrin function during injury, regeneration, and differentiation of kidney tubular epithelial cells at the molecular level. In Specific Aim 1, an examination of the modulation of integrin ligand-binding activity, expression, and distribution in kidney cell lines subjected to ATP-depletion will be carried out. In addition, basolateral targeting signals in integrins will be identified, and the distribution of integrin alpha and beta subunits in the ischemic rat kidney will be examined. In Specific Aim 2, the role of Forssman antigen in laminin adhesion, cell polarization, and morphogenesis will be examined through reconstitution studies, biological assays, and antisense approaches. The expression of laminin isotypes in kidney cell lines during tubulocyst formation and after mechanical injury, and in the post-ischemic rat kidney will also be determined. Finally, the involvement of integrins and laminin in epithelial cell polarization will be tested through the expression of antisense and dominant-negative constructs.