The overall goal of this project will be to continue to characterize the physiology and pathophysiology of childhood growth by a coordinated basic science and clinical research effort into the structure and function of growth promoting hormones and their receptor. Specifically, we aim to: a) Characterize the structure and function of the entire IGF I gene, including its promoter and regulatory regions, determine the mechanisms by which growth hormone activates IGF I gene transcription, and determine whether mutations in the growth hormone regulatory region of the gene are responsible for disorders of growth. b) Characterize the expression of the IGF genes in fetal rat kidney and define the roles of the insulin-like growth factors in embryonic kidney development. c) Characterize structural modifications of the IGF I receptor and define the formation of functional domains during post-translational processing of the receptor. d) Characterize abnormalities in growth hormone and insulin-like growth factor structure and action, including the roles of growth hormone and IGF I binding proteins in the pathophysiology of various types of growth failure. e) Quantify daily energy expenditure, body protein dynamics, and glucose and amino acid sensitivity to the actions of insulin in slowly growing children and assess the relationships between these variables and the acute and chronic responses to growth hormone treatment.
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