Although growth retardation is a serious complication in children with chronic renal failure (CRF), its pathogenesis is poorly understood. The long-term goal of this research is to develop therapeutic strategies for the prevention and treatment of growth retardation in children with CRF based on understanding of its molecular pathophysiology. Using a primary culture of tibial epiphyseal chondrocytes in a rat model of growth retardation in CRF, growth hormone (GH) and insulin-like growth factor(IGF)-I resistance in cellular growth responses have been demonstrated. Two specific molecular defects in the GH-IGF-I axis have been identified in CRF chondrocytes. Growth hormone receptor(GHR) mRNA (Northern blot) and protein (immunoblot) are both decreased in CRF chondrocytes and may account for GH resistance. Intracellular phosphatidyl-inositol(PI) 3 kinase protein (85 kDa subunit) is decreased in CRF chondrocytes and may account for IGF-I resistance. Mechanisms underlying these molecular abnormalities will be studied in CRF. Experiments will be designed to test the roles of elevated GH and adrenal glucorticoids as well as 1,25 vitamin D3 deficiency in the pathogenesis of the GH-IGF-I defects in CRF. The hypothesis, that these molecular defects in GH-IGF-I axis are important in the pathogenesis of GH, IGF-I resistance and growth retardation in CRF chondrocytes, will be tested. The role of the local GH-IGF-I axis in CRF chondrocytes will be examined by measuring IGF-I mRNA generation with GH stimulation as well as growth responses with GH and IGF-I antibody co-incubation in both CRF and control chondrocytes. The effects of specific inhibition of PI3 kinase (by wortmannin) on growth response and IGF-I sensitivity will be examined in normal chondrocytes. The local role of GH-IGF-I axis, in the face of these dual molecular defects in CRF, will be integrated at molecular and autocrine/paracrine levels. Finally in vitro gene transfer studies using fusion genes of GHR (and PI3 kinase) and a reporter gene with a lipofectin system will be performed to examine if normalization of these molecular abnormalities will lead to correction of GH, IGF-I resistance, and growth retardation in CRF chondrocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050780-05
Application #
6177499
Study Section
Special Emphasis Panel (ZRG4-GMB (04))
Program Officer
Hirschman, Gladys H
Project Start
1997-05-01
Project End
2002-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
5
Fiscal Year
2000
Total Cost
$135,836
Indirect Cost
Name
Oregon Health and Science University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Mak, Robert H; Cheung, Wai W; Gertler, Arieh (2014) Exploiting the therapeutic potential of leptin signaling in cachexia. Curr Opin Support Palliat Care 8:352-7
Mak, Robert H; Cheung, Wai W; Roberts Jr, Charles T (2008) The growth hormone-insulin-like growth factor-I axis in chronic kidney disease. Growth Horm IGF Res 18:17-25
Mak, Robert H; Cheung, Wai (2007) Adipokines and gut hormones in end-stage renal disease. Perit Dial Int 27 Suppl 2:S298-302
Cheung, Wai W; Kuo, Huey-Ju; Markison, Stacy et al. (2007) Peripheral administration of the melanocortin-4 receptor antagonist NBI-12i ameliorates uremia-associated cachexia in mice. J Am Soc Nephrol 18:2517-24
Mak, Robert H; Cheung, Wai (2007) Cachexia in chronic kidney disease: role of inflammation and neuropeptide signaling. Curr Opin Nephrol Hypertens 16:27-31
Mak, Robert H; Cheung, Wai; Purnell, Jonathan (2007) Ghrelin in chronic kidney disease: too much or too little? Perit Dial Int 27:51-5
Mak, Robert H; Cheung, Wai; Cone, Roger D et al. (2006) Mechanisms of disease: Cytokine and adipokine signaling in uremic cachexia. Nat Clin Pract Nephrol 2:527-34
Murray, J F; Hahn, J D; Kennedy, A R et al. (2006) Evidence for a stimulatory action of melanin-concentrating hormone on luteinising hormone release involving MCH1 and melanocortin-5 receptors. J Neuroendocrinol 18:157-67
Mak, R H; Cheung, W; Cone, R D et al. (2006) Leptin and inflammation-associated cachexia in chronic kidney disease. Kidney Int 69:794-7
Cheung, Wai; Yu, Pin X; Little, Brian M et al. (2005) Role of leptin and melanocortin signaling in uremia-associated cachexia. J Clin Invest 115:1659-65

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