APICAL IF MEDIATE POST-ISCHEMIA RECOVERY IN EPITHELIA

描述（改编自申请人的摘要）：缺血是一个主要原因 急性肾功能衰竭（ARF），也是一个重要的原因， 其他上皮器官，如肝脏和肠，特别是在 移植上皮细胞的缺血性损伤具有复杂的多重性， 方面的影响.然而，有一个共识，即质膜极性的丧失， 由细胞骨架的解体引起的是主要的 上皮功能衰竭的病理生理机制。最近 该领域的研究集中在对肌动蛋白细胞骨架的影响， 尽管已有报道，微管也在 再灌注申请人的实验室最近表明， 中间丝在组织中起着重要的作用， 顶极，通过维持F-肌动蛋白微绒毛核心的稳定性和 微管的组织。在这方面，他刚刚报告说， 顶端IF网络维持微管组织中心的位置 初步数据表明，IF网络是 在ATP耗尽期间稳定，且在ATP耗尽期间MTOC与其分离。 此外，通过敲除CK 8基因的转基因技术， 末端网确实是顶端极性所必需的。这些数据 提供了一个假设的基础，其中顶端IF网络是 在ATP耗尽后，负责MTOC通过 功能的IF相关蛋白，或者，直接通过结合 与细胞角蛋白有关。为了检验这一假设，具体目标是： 1)研究IF蛋白对细胞骨架重建的特异性， ATP耗竭。 2)表征参与恢复微管极性的蛋白质， 上皮细胞缺血性损伤及其ATP介导的分子变化 耗尽 这个项目的长期目标是确定分子机制 介导MTOC从中间细丝的分离，以确定可能的 治疗替代品来阻止它们，从而保护上皮细胞 或促进其恢复。

DESCRIPTION (Adapted from the Applicant's Abstract): Ischemia is a major cause of acute renal failure (ARF), and also an important cause of dysfunction in other epithelial organs such as liver and intestine, especially after transplantation. The ischemic injury in epithelial cells has complex multiple effects. However, there is a consensus in that loss of plasma membrane polarity resulting from the disorganization of the cytoskeleton is one of the major pathophysiological mechanisms for epithelial function failure. Most recent research in this area has focused in the effects on the actin cytoskeleton, although it has been reported that microtubules are also disorganized during reperfusion. The applicant's lab has recently shown that the apical network of intermediate filaments plays a substantial role in the organization of the apical pole, by maintaining the stability of F-actin microvillus cores and the organization of microtubules. In this regard, he has just reported that the apical IF network maintains the position of Microtubule Organizing Centers (MTOC) that bind it. The preliminary data indicate that the IF network is stable during ATP depletion and that MTOC detach from it during ATP depletion. Furthermore, using a transgenic knock-out of the CK8 gene, he have demonstrated that the terminal web is indeed required for apical polarity. These data provide the foundation for a hypothesis where the apical IF network is responsible for the re-localization of MTOC after ATP depletion through the function of IF-associated proteins, or, alternatively, directly through binding to the cytokeratins. To test this hypothesis, the specific aims are: 1) Study the specificity of IF proteins to re-polarize the cytoskeleton after ATP depletion. 2) Characterize the proteins involved in regaining microtubule polarity after an ischemic injury in epithelia cells and their molecular changes during ATP depletion. The long term goals of this project are to identify the molecular mechanisms mediating the detachment of MTOC from intermediate filaments to define possible therapeutic alternatives to block them and, therefore, protect epithelial cells from ischemic injury or promote their recovery.