Current hGH (human growth hormone) therapy, approved for the treatment of pituitary dwarfism, requires chronic administration by injection and is exceedingly expensive (up to $30,000 per patient annually). This project focuses on the discovery of novel low molecular weight pharmaceuticals which act by transcriptional activation of the endogenous hGH gene. In Phase I, the promoter and first intron of the hGH gene were cloned and fused to a luciferase reporter vector. We also cloned the promoter of a homologous gene termed hGHN. Both of these promoter-reporter constructs exhibited extreme tissue specificity, showing more than a thousand-fold greater activity in pituitary cells than in fibroblasts. Regulation by known modulators of hGH transcription was also observed, confirming that these vectors faithfully represented the transcriptional regulation of the endogenous hGH gene. In Phase II, stably transfected cell lines will be used to search for compounds which transcriptionally activate the hGH gene; specifically, for compounds which act either as GHRF (growth hormone releasing factor) agonists or act directly via the GH transcription factor, Pit-1. The primary screen will employ a unique, fully automated robotic screening system which enables over 100,000 compounds to be screened per year. Lead compounds will be sought from a collection of fungal fermentation broths and from combinatorial peptide libraries.
