Children with chronic renal failure (CRF) grow poorly. Linear growth occurs in bone growth plates and reflects a balance between actions of growth simulators such as growth hormone (GH) and insulin-like growth factors (IGFs), and growth inhibitors. In normal sera, IGF binds IGF binding protein (IGFBP)-3 and acid-labile subunit (ALS) in a large complex; proteolysis of this IGFBP-3 releases IGFs to act on targets such as growth plates. In CRF sera this process is normal, but excess small IGFBPs may block IGF action by binding released IGF. IGFBP-1 and -2 block IGF action in cell culture; levels of each are high in CRF sera and correlate with growth failure. In CRF children, GH increases growth, the amount of IGFBP-3 in the large complex and the amount of IGF released by the complex; this increased release of IGFs appears to overcome the high level of inhibitory IGFBPs. In this proposal, the first goal is to identify IGFBPs that are growth inhibitors, potentially in CRF. In part one of this goal (Specific Aim #1), newly assayable, intact IGFBP-4 will be measured in CRF sera from children to see if levels correlate with growth failure. Part two of this goal (Specific Aim #2) investigates how excess IGFBPs affect growth. It includes experiments in which chick cartilage will be exposed to IGFBP-2 and IGFBP-3 (fragments), in vitro, and in vivo studies in which rats will be exposed to excess IGFBP-2 by injection, or mice to excess IGFBP-2 or -3 by overexpression of the human transgenes. The second goal (Specific Aim #3) is to see how IGFBP-3 releases IGFs to tissue; purified IGFBP-3 and ALS will be used to identify proteases such as plasminogen that bind to and digest IGFBP-3, and to determine how they do so. The third goal (Specific Aim #4) is to see if high cytokine concentrations lead to high levels of inhibitory IGFBP-1 and -2, perhaps revealing a mechanism for CRF-induced excesses in IGFBPs. The fourth goal (Specific Aim #5) is to grow larger IGFBP-1:IGF-I crystals which should result in an understanding of how IGFBPs bind IGFs. Identifying inhibitory IGFBPs, how they bind IGFs, and how their production is regulated may suggest clinical ways to improve IGF action by either lowering IGFBP production or by blocking IGFBP binding to IGFs. Understanding how IGFBP-3 and proteases interact to release IGFs may suggest new ways to liberate IGFs from IGFBP-3 in order to promote anabolic effects in a clinical setting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK038773-12A1
Application #
2620316
Study Section
General Medicine B Study Section (GMB)
Project Start
1986-09-01
Project End
2001-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
12
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Kiepe, Daniela; Ulinski, Tim; Powell, David R et al. (2002) Differential effects of insulin-like growth factor binding proteins-1, -2, -3, and -6 on cultured growth plate chondrocytes. Kidney Int 62:1591-600
Modric, T; Silha, J V; Shi, Z et al. (2001) Phenotypic manifestations of insulin-like growth factor-binding protein-3 overexpression in transgenic mice. Endocrinology 142:1958-67
Scheimann, A O; Durham, S K; Suwanichkul, A et al. (2001) Role of three FKHR phosphorylation sites in insulin inhibition of FKHR action in hepatocytes. Horm Metab Res 33:631-8
Silha, J V; Gui, Y; Modric, T et al. (2001) Overexpression of the acid-labile subunit of the IGF ternary complex in transgenic mice. Endocrinology 142:4305-13
Conover, C A; Bale, L K; Durham, S K et al. (2000) Insulin-like growth factor (IGF) binding protein-3 potentiation of IGF action is mediated through the phosphatidylinositol-3-kinase pathway and is associated with alteration in protein kinase B/AKT sensitivity. Endocrinology 141:3098-103
Powell, D R; Liu, F; Baker, B K et al. (2000) Effect of chronic renal failure and growth hormone therapy on the insulin-like growth factors and their binding proteins. Pediatr Nephrol 14:579-83
Suwanichkul, A; Boisclair, Y R; Olney, R C et al. (2000) Conservation of a growth hormone-responsive promoter element in the human and mouse acid-labile subunit genes. Endocrinology 141:833-8
Durham, S K; Suwanichkul, A; Scheimann, A O et al. (1999) FKHR binds the insulin response element in the insulin-like growth factor binding protein-1 promoter. Endocrinology 140:3140-6
Durham, S K; Suwanichkul, A; Hayes, J D et al. (1999) The heparin binding domain of insulin-like growth factor binding protein (IGFBP)-3 increases susceptibility of IGFBP-3 to proteolysis. Horm Metab Res 31:216-25
Campbell, P G; Durham, S K; Hayes, J D et al. (1999) Insulin-like growth factor-binding protein-3 binds fibrinogen and fibrin. J Biol Chem 274:30215-21

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