During my Post-doctoral training in Pediatric endocrinology and subsequent experience as a starting assistant professor at the University of California San Francisco (UCSF), I have developed and pursued a primary interest in growth disorders of childhood, and in particular, factors involved in the regulation of growth hormone (GH) and the GH-dependent insulin-like growth factors (IGFs) or somatomedins (Sm). IGFs have been shown to have an important role in post-natal somatic growth, and have also been implicated in the regulation of fetal growth. Since IGFs exert their effects by interacting with specific cell-surface receptors, it is hypothesized that a receptor defect could result in impaired IGF responsiveness and thus be a cause of growth failure. Previous attempts to identify children with IGF-I receptor defects have utilized competitive binding studies and measurements of receptor responsiveness, and suggest that IGF-I receptor defects constitute a heterogeneous group of disorders. The specific goals to be accomplished during the grant period are directed towards the study of the synthesis and regulation of the IGF-I receptor at the molecular level, and include the following: (1) to identify a cDNA for the IGF-I receptor by screening a human cDNA library with synthetic oligonucleotide probes based on the published cDNA sequence; (2) to use this cDNA as a probe of IGF-I receptor gene expression by measuring steady state mRNA levels in fibroblasts from children with growth disorders; (3) to correlate mRNA levels with measurements of a) 125I-IGF-I binding, b) receptor biosynthesis using a specific monoclonal antibody against the IGF- I receptor, and c) IGF-I induced aminoisobutyric acid uptake and thymidine incorporation in fibroblasts from children with growth disorders; and (4) to characterize the effects of hormonal factors known to influence growth, including glucocorticoids, sex steroids, thyroid hormones, IGF-I, and insulin, on IGF-I receptor gene expression in fibroblasts from normal subjects. These studies will be carried out in children referred to the pediatric endocrinology service, a major referral center for childhood growth disorders, supervised by Drs. Melvin Grumbach and Selna Kaplan. Cellular and molecular studies will be carried out under the supervision of Dr. Ira Goldfine in the Cell Biology Laboratory at Mt. Zion Hospital, a UCSF affiliate. These biochemical studies may lead to further understanding ,f the role of the IGF-I receptor in normal and abnormal growth.
