The mechanisms by which hormones and growth factors stimulate the somatic growth of the fetus are poorly understood. Most of the classical hormones that stimulate postnatal growth appear to have little influence on the fetus. In this proposal, which is based on the supposition that peptide growth factors are important mediators of fetal growth, emphasis is placed on determining the role of the somatomedins in this process. We have extensive experience with fetal and postnatal studies of the growth hormone dependent mitogen, somatomedin-C/insulin-like growth factor I (Sm-C/IGF-I). We propose to continue these studies and to incorporate parallel research on insulin-like growth factor II. Using animal models for intrauterine and neonatal growth retardation we will attempt to define the relationships among somatic growth, serus and tissue concentrations of the somatomedins, and growth hormone binding. Because there is growing evidence that the somatomedins act through autocrine and/or paracrine mechanisms, we propose to determine concentrations of the somatomedins in human fetuses and neonates, and to relate these measurements to serum concentrations and growth. We will carry out experiments designed to define the intracellular forms of the somatomedins in the fetus, and we will continue work directed at defining the chemical nature, physiological regulation and biologic actions of somatomedin binding proteins. Using cDNA probes for the somatomedins, we will carry out studies of cellular localization of expression of the Sm-C/IGF-I gene by in situ cDNA/mRNA hybridization, in parallel with immunocytochemical studies of somatomedin. We will then proceed to quantify concentrations of somatomedin mRNAs in fetal rat and human tissues. In this way we hope to determine the sites and ontogeny of fetal somatomedin syntheses. In addition, we plan to characterize somatomedin gene polymorphism in disorders causing intrauterine growth retardation. Finally, we will continue studies using our recently described ubiquitin precursor cDNA probe. These will be directed at determining changes in ubiquitin mRNA through development and defining factors that regulate expression of ubiquitin genes during development. Ubiquitin's unique role in protein degradation and possible role in transcription make it likely to be important during fetal growth and development.
Showing the most recent 10 out of 104 publications
