Although gastrin, CCK and substance P are medically important hormones that have been well studied with regard to structure and physiology, very little is known about the molecular mechansims which regulate their synthesis. The main objective of the proposed research is to further our understading of the molecular events controlling the metabolism and biosynthesis of these hormones by examining the regulation of expression of their genes. The experiments outlined in this proposal include the following areas of investigation: (a) Gastrin, CCK and substance P specific cDNA clones will be isolated and their precursor sequences will be determined. (b) Expression of gastrin, CCK and substance P clones will be attempted in E. coli. (c) Gastrin, CCK and substance P precursor polypeptides will be isolated and used in the study of processing-modification in vivo as well as in vitro. (d) Analogs of gastrin, CCK and substance P precursor will be generated by altering cDNA clones. (e) Isolate and characterize chromosomal genes for gastrin, CCK and substance P. (f) Study the mechanism of initiation of transcription and RNA processing. Since gastrin, CCK and substance P are associated with human diseases, namely gastric carcinoma, obesity and Huntington's and Parkinson's diseases respectively, understanding of the mechanisms which regulate their synthesis may ultimately provide useful new insights into the cause and management of these diseases.
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