CHEMICAL PATHOLOGY AND RENAL REPAIR

组织修复在生物反应中起着重要的作用， 环境化学物质引起的肾毒性损伤， 活性化学物质 肾脏是化学药物的主要目标 毒素，因为它在异生物质代谢中的作用。 虽然， 肾毒素激活和细胞毒性变得越来越清楚， 对化学损伤的修复机制知之甚少。 我们知道， 近端小管上皮细胞通过替换死亡的 细胞通过，剩余细胞的增殖，然而，我们不知道 是什么控制了增殖反应 自从修复组织 在整个过程中，损伤可能与激活步骤同等重要 肾脏对环境毒素的反应，重要的是 了解修复过程。 有了这些知识，我们未来的目标将是 评估持续暴露于环境污染物的影响 修复过程本身。 这一点至关重要，因为环境 接触往往是慢性的，而不是急性的， 修复可能导致器官损伤。 我们的目标是阐明肾脏组织修复的机制 （肾源性修复）。 我们建议监管机构，包括增长因素 和细胞外基质，控制修复过程的阶段：1） 进入细胞周期，2）细胞生长，3）生长停止，和 4)分化 已经建立了体内每个阶段的标志物 培养大鼠肾近曲小管上皮细胞的方法 它们表达相同的生长和分化标记 适当地。 因此，体内和体外方法的组合 将用于协助调查，并进行交叉检查和核实 结果 与各时相相关的生长因子表达变化 肾源性修复（通过标记物鉴定）将在体内确定 使用cDNA探针和/或抗体。 一旦这些因素 确定了它们控制细胞生长的机制， 可以使用组织培养模型在体外阐明分化。 蛋白激酶作为生长因子的调节剂起主要作用 因此，蛋白激酶在肾修复中的作用将 被确定。 具体而言，生长因子调节的底物 将在肾上皮细胞中鉴定蛋白激酶。 最后， 细胞外基质在控制肾细胞功能中的作用 将通过确定以下表达式来进行评估： 通过培养的肾上皮细胞的分化标志物。

Tissue repair plays an important role in the biological response to nephrotoxic damage by environmental chemicals which are activated to reactive chemical species. The kidney is a major target for chemical toxins due to its role in xenobiotic metabolism. Though the mechanisms of nephrotoxin activation and cellular toxicity are becoming more clear, the mechanism for repair of chemical damage are poorly understood. We do know, that the proximal tubule epithelial cells repair damage by replacing dead cells through, proliferation of remaining cells, however, we do not know what controls the proliferative response. Since repairing the tissue damage may be of equal importance to the activation step in the overall response of the kidney to environmental toxins, it is important to understand the repair process. With this knowledge, our future goal will be to assess the effect of continued exposure to environmental pollutants on the repair process itself. This is critical since environmental exposure tend to be chronic rather than acute, and the ability to inhibit repair may contribute to organ damage. Our goal is to elucidate the mechanisms of tissue repair in the kidney (nephrogenic repair). We propose that regulators, Including growth factors and extracellular matrix, control the phases of the repair process: 1) entry into the cell cycle, 2) growth of cells, 3) cessation of growth, and 4) differentiation. Markers for each phase in vivo have been established as has a method for culturing rat kidney proximal tubule epithelial' cells which express the same markers for growth and differentiation appropriately. Therefore, a combination of in vivo and in vitro approaches will be used to facilitate the investigations and to cross-check and verify results. Changes in growth factor expression associated with each phase of nephrogenic repair (as identified by markers) will be determined in vivo using cDNA probes and/or antibodies. Once these factors have been identified, the mechanisms through which they control cell growth and differentiation can be elucidated in vitro using the tissue culture model. Protein kinases play a major role as regulators of growth factor action, therefore,, the role of protein kinases in nephrogenic repair will be determined. Specifically, substrates for growth factor-regulated protein kinases will be identified in kidney epithelial cells. Finally, the role of extracellular matrix in controlling the ability of kidney cells to differentiate will be evaluated by determining the expression of differentiation markers by the cultured renal epithelial cells.