IGF-I RESISTANCE IN CHRONIC UREMIA

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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.