POLYPEPTIDE GROWTH FACTORS AND RENAL DEVELOPMENT

多肽生长因子和肾脏发育

• 批准号: 6105519
• 负责人: Marc Randall Hammerman
• 金额: $ 12.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6105519
• 关键词: CD44 molecule; acute renal failure; cardiovascular disorder chemotherapy; chemical binding; gene induction /repression; growth /development; integrins; kidney disorder chemotherapy; laboratory rat; nonhuman therapy evaluation; osteopontin; renal ischemia /hypoxia

The restoration of function following ischemic acute renal failure (ARF) occurs through a series of events whereby dedifferentiated proximal tubule cells proliferate and migrate into the denuded area of the basement membrane. The loss of differentiated character and the appearance of embryonic markers in the regenerating cells reflect similarities between repair and development. Changes in the renal expressions of several growth factors occur following ARF. Three of them, when administered exogenously to rats rendered ischemic, ameliorate the course of ARF. Consistent with the similarities between repair and development, the same or homologous growth factors are expressed in developing kidney and play key roles in vitro. To determine whether growth factors stimulate the expression of genes in kidney, the products of which are important effectors of the regenerative response, we identified genes, the expressions of which in kidney are enhanced by induction of ARF and further enhanced by the administration of IGF I. One such gene product was identified as osteopontin, suggesting that osteopontin plays an important role in renal regeneration following ARF, and by inference, in development. Accordingly, the specific aims of the present proposal are: l) to define the expression of osteopontin and its binding sites to include the alpha(v)beta(3) integrin and the CD44 receptor in kidneys following induction of ARF in rats; 2) to define the expression of osteopontin and its binding sites in rat kidneys during development; 3) to define the consequences of blocking osteopontin activity on development in vitro and to characterize the mechanism of its effect during the process of recovery following ARF; and 4) to determine whether the administration of osteopontin to rats with ARF ameliorates the course of injury. Our studies will test the hypothesis that the expression of osteopontin in kidney is essential for regeneration following ARF, will shed light on the role of osteopontin and its receptors in this process, will test the hypothesis that osteopontin plays a key role in kidney development, and will provide insight into a novel therapeutic modality that may be useful to treat ARF.

缺血性急性肾衰竭后功能的恢复 （ARF）通过一系列事件发生，从而推导 近端小管细胞增殖并迁移到 地下膜。差异性角色的丧失 再生细胞中胚胎标记物的出现反射 维修和开发之间的相似之处。肾脏变化 ARF后发生了几种生长因素的表达。三个 当它们外源对呈缺血性的大鼠外源时， 改善ARF的过程。与相似之处一致 维修和开发，相同或同源的增长因素是 以发展肾脏并在体外发挥关键作用表示。到 确定生长因子是否刺激基因在 肾脏，其产物是重要的效应子 再生反应，我们确定了基因，其表达在 通过诱导ARF增强肾脏，并进一步增强 IGF I的施用。一种这样的基因产物被确定为 骨桥，表明骨桥蛋白在 ARF之后的肾脏再生，并通过推断开发。 因此，本提案的具体目的是：l） 定义骨桥蛋白及其结合位点的表达以包括 Alpha（V）β（3）整合素和肾脏中的CD44受体随后 大鼠ARF的诱导； 2）定义骨桥的表达 及其在发育过程中大鼠肾脏中的结合位点； 3）定义 阻止骨桥蛋白活动对发展的后果 体外并表征其在 ARF之后的恢复过程； 4）确定是否 给有ARF大鼠的骨桥蛋白施用可以改善课程 受伤。我们的研究将检验以下假设 肾脏中的骨桥蛋白对于ARF后再生至关重要，将 阐明了骨桥蛋白及其受体在此的作用 过程，将检验骨桥蛋白在 肾脏发育，并将洞悉一种新颖的治疗性 可能对治疗ARF有用的方式。