Children with chronic renal failure (CRF) grow poorly; the CRF state interferes with the hormonal control of linear growth, and may interfere with the general function of specific growth factors. Growth hormone (GH) and insulin-like growth factor (IGF)-I promote linear growth by synergistically stimulating mitogenic pathways in growth-plate chondrocytes. GH and IGF-I levels are normal in CRF serum, and IGF-I is bioactive. However, CRF serum contains an excess of proteins, the IGF binding proteins (IGFBPs), which can compete with cell-surface receptors for IGF-I binding and in this way inhibit IGF-I action. Two specific IGFBPs (IGFBP-1 and a 33 kiloDalton or kD IGFBP), and perhaps a third (IGFBP-3), contribute to this CRF pool of proteins which bind free IGF-I. IGFBP-1 is clearly, and the 33 kD IGFBP is probably, a potent inhibitor of IGF-I action in vitro. The overall objective of this proposal is to study the role of IGFBPs as IGF-I inhibitors in CRF; it is anticipated that this work will suggest (i) which IGFBPs inhibit linear growth, and (ii) how to reverse the inhibition. Specific antisera will determine if the 33 kD IGFBP is IGFBP-2, a potent IGF-I inhibitor. Specific antisera, gel filtration, and (125)I-IGF-I binding studies will also (i) determine the size and bioactivity of a potentially growth-stimulating IGFBP (IGFBP-3) found in excess in CRF serum by RIA; and (ii) characterize IGFBPs in peritoneal dialysate, since this will indicate which IGFBPs are in the extravascular space and are thus able to inhibit IGF-I acting by paracrine or autocrine mechanisms. Children entered in a multicenter trial of GH therapy for CRF-related growth failure will also be studied. Changes in serum IGFBP profiles will be related to growth response and whether GH was givnen; it is anticipated that levels of inhibitory IGFBPs (e.g. IGFBP-1) will fall with GH and improved growth. Effects of IGFBPs on growth and growth-plate cartilage in vivo will be tested by treating growing rats with IGFBPs purified from cultured cells or by overexpression of cloned IGFBP genes. Finally, the mechanism behind high IGFBP levels in CRF will be studied by measuring IGFBP mRNA levels in a rat CRF model, and by studying the effect of purported low MW inhibitors of IGF-I action on a tissue culture model of hepatic IGFBP-1 production.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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General Medicine B Study Section (GMB)
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Baylor College of Medicine
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