The studies proposed are extensions of ongoing research in this laboratory to determine the physiological role of the somatomedins in growth and differentiation. During the next four years we will pursue this goal along 2 major lines: We will address the molecular mechanisms by which the somatomedins interact with growth hormone and other hormones to produce their biologic effects, and we will focus on the rat as a model to obtain an integrated picture of the mechanisms governing the regulation and expression of the gene for Sm-C/IGF-I and for those of its receptor and the somatomedin binding protein(s). The studies we propose on mechanisms of somatomedin action will be designed to critically examine the """"""""dual effector theory"""""""" of growth hormone action proposed by Dr. Howard Green as opposed to our concept that the role of the somatomedins is to amplify the actions of growth hormone and other hormones on both cell differentiation and replication. We will study the interactions of GH and Sm-C/IGF-I in 3T3 preadipocytes, and in growth plate cartilage, and the mechanisms by which Sm-C/IGF-I amplifies the actions of FSH in the Sertoli and granulosa cells and TSH in thyroid cultures. We will complete the characterization of the rat Sm-C/IGF-I gene and explore the roles of the 5' and 3' flanking regions in gene expression. We will determine which portions of the rat Sm- C/IGF-I gene correspond to each of the multiple Sm-C/IGF-I mRNAs in rat tissues, and study the effect of growth hormone on the expression of these mRNAs and the mRNAs that code for the rat hepatocyte binding protein and type-I receptor, and determine the tissue and cellular localization of these mRNA's by Northern blot analyses and in situ hybridization histochemistry. We will isolate sufficient quantities of the rat hepatocyte binding protein to determine what role, if any, this substance may play in the post-translational processing of the somatomedin gene products, and how it may modify the biological effects of somatomedin on growth and differentiation.
