IGF-I RESISTANCE IN CHRONIC UREMIA

描述(直接取自申请人的摘要) 尿毒症生长迟缓的部分原因是对 生长激素和IGF-I。虽然对IGF-I的抵抗在很大程度上是 归因于循环抑制物的积累，特别是 胰岛素样生长因子结合蛋白(IGFBPs)的最新研究 尿毒症大鼠提示耐药性也可能是由于IGF-I的缺陷所致 受体介导的信号转导。组织中的这种缺陷是否 慢性尿毒症儿童是否有反应性尚不清楚。在这 建议的研究，首先在尿毒症大鼠身上进行，然后在肌肉上进行 从尿毒症儿童身上获得的活检，我们的总体目标是获得 对胰岛素样生长因子-I抵抗的机制认识 先进的CRF。我们将检验假设，在CRF中对IGF-I的抵抗 IGF-I受体介导受损的骨骼肌发育 信号转导和改变局部IGFBP的产生。另外，这是一种损害 局部IGF-I的产生与尿毒症组织生长迟缓有关。 为了测试我们的假设，我们的目标是解决以下具体问题 问题：1)对IGF-I对骨骼肌作用的抵抗 进展期慢性肾功能衰竭患者发生蛋白质周转？2)有 慢性肾功能衰竭IGF-I受体信号转导通路的变化 导致IGF-I抵抗？3)骨骼肌IGFBPs是否有变化 会导致IGF-I抵抗吗？4)骨骼有缺陷吗？ 肌肉IGF-I的产生可能有助于尿毒症组织的生长 智障？ 这些研究是在未成熟的慢性尿毒症大鼠和 取自终末期肾病患儿的分离骨骼肌 疾病，应该为IGF-I抵抗的机制提供新的见解 从而更好地了解尿毒症的发病机制。 发育受阻。从长远来看，这些信息将有助于推进我们的 制定战略以优化管理的总体目标 患有慢性肾衰的儿童。

DESCRIPTION (Taken directly from applicant's abstract) Uremic growth retardation is caused in part by resistance to the action of growth hormone and IGF-I. While resistance to IGF-I has largely been attributed to the accumulation of circulating inhibitors, especially the insulin-like growth factor binding proteins (IGFBPs), recent studies in uremic rats suggest that resistance may also be due to a defect in IGF-I receptor mediated signal transduction. Whether such a defect in tissue responsiveness occurs in children with chronic uremia is not known. In this proposed study, carried out initially with uremic rats and then with muscle biopsies obtained from uremic children, our overall aim is to gain a mechanistic understanding of the resistance to IGF-I that develops in advanced CRF. We will test the hypothesis that in CRF resistance to IGF-I develops in skeletal muscle because of impaired IGF-I receptor mediated signal transduction and altered local IGFBP production. Also, that impaired local IGF-I production contributes to the retarded tissue growth of uremia. In order to test our hypotheses we aim to address the following specific questions: 1) does resistance to the action of IGF-I on skeletal muscle protein turnover develop in advanced chronic renal failure? 2) are there changes in the IGF-I receptor signal transduction pathway in CRF that could cause IGF-I resistance? 3) are there changes in skeletal muscle IGFBPs that could result in IGF-I resistance? and 4) is there a deficit in skeletal muscle IGF-I production that could contribute to uremic tissue growth retardation? These studies carried out with immature chronically uremic rats and with isolated skeletal muscle obtained from children with end-stage renal disease, should provide new insights into the mechanism of IGF-I resistance and, thus, lead to a better understanding the pathogenesis of uremia impaired growth. In the long term this information will help advance our overall objective of developing strategies to optimize the management of children with CRF.