CORE--RENAL INJURY MODEL

本核心的总体目标是开发和定义体内实验系统，该系统可以测试蛋白质-蛋白质相互作用（单个项目在细胞水平上的主要焦点）如何在缺血和缺氧损伤期间在完整动物的整个肾脏中被破坏，以及在恢复过程中恢复正常肾脏结构（和功能）的机制。虽然了解单个细胞膜蛋白如何在分子水平上与特定的细胞骨架元件相互作用以及这些相互作用在ATP消耗过程中如何被破坏是很重要的，但有必要在不同的组织水平上分析这些变化，包括细胞、器官和整个动物，以充分了解它们的病理生物学重要性。这一原则在所谓的敲除实验中得到了清楚的证明，在整个动物水平上的结果往往没有预期的那么引人注目，这表明了在孤立细胞培养系统中无法完全理解的复杂性和冗余程度。在体内模型中，细胞和系统过程都需要实现完全功能的生理恢复，并了解血管和上皮结构、生长因子和细胞因子、血流动力学和细胞改变之间的相互关系，这些变化可以影响对损伤和恢复的反应性质。因此，动物模型提供了唯一的方法，可以确定发生在缺血性肾损伤和恢复的关键组成部分的特定分子和细胞反应的整合、相对重要性和层次。该中心提供的动物模型将为基础细胞和分子生物学研究应用于急性肾功能衰竭的临床问题提供一个中心。

Description: (Adapted from the application) The overall objective of this Core is to develop and define in vivo experimental systems which can test how the protein-protein interactions which are the main focus of the individual projects at the cellular level are disrupted in the whole kidney of the intact animal during ischemic and hypoxic injury and the mechanisms by which normal renal structure (and function) is restored during recovery. While it is important to understand how individual cell membrane proteins interact with specific cytoskeletal elements on a molecular level and how these interactions are disrupted during ATP depletion, it is necessary to analyze these changes at different levels of organization including the cellular, organ and whole animal to fully understand their pathobiological importance. This principle has been clearly demonstrated in so called knockout experiments where more often than not the result at the whole animal level is less dramatic than anticipated, demonstrating a level of complexity and redundancy which cannot be appreciated fully in isolated cell culture systems. In an in vivo model both cellular and systemic processes are needed to achieve full functional physiologic recovery and to understand interrelationships between vascular and epithelial structures, growth factors and cytokines and hemodynamic and cellular alterations which can influence the nature of response to injury and recovery. Thus, animal models provide the only way that the integration, relative importance and hierarchy of the specific molecular and cellular responses that occur in ischemic renal injury and in the critical components of recovery can be determined. The provision of animal models by the core will provide a center for the application of basic cell and molecular biologic studies to the clinical problem of acute renal failure.