) We propose to study the molecular epidemiology of PTHrP in prostate cancer. This will be accomplished by studying the regulation of the production and the growth-promoting effects of PTHrP in human prostate cancers. We and others have demonstrated that PTHrP production by cancer cells can provide novel serum and tissue markers for the presence and extent of disease. More relevant to his application, this cancer cell product and its derivatives contribute to the microenvironment of the malignancy and can regulate growth and function. We shall study the cellular, molecular, and clinical biology of PTHrP in prostate cancer cells. We shall conduct our studies in several types of cell preparartions; cell lines that we have established in our laboratory, primary cell cultures, and newer methods of cell culture. Our general approach will be to use cell lines for more preliminary studies and to use the primary cultures for the more relevant questions that become focused by the preliminary studies. We shall identify the effects of PTHrP and its derived peptides on cell growth and elucidate the mechanisms of the regulation of the gene transcription, translation, processing, and secretion of PTHrP. We shall elucidate the molecular mechanisms by which the production of these PTHrPs is regulated by the PTHrPs, themselves, and by classical and newly-appreciated growth factors. The molecular mechanisms of regulation to be studies include gene expression, translation, and secretion.
Our specific Aims are to: determine the molecular forms of PTHrP that are produced by prostate cells and identify their clinical correlates, determine the effects of PTHrP and its peptides on the growth and malignant transformation of prostate cells, identify the molecular mechanisms of PTHrP secretion and messenger ribonucleic acid (mRNA) regulation in the prostate, and identify the transcriptional mechanisms of PTHrP gene expression in the prostate. The methods to be used include immunoassay, immunohistology, polymerase chain reaction (PCR), and transfection analysis of promoter- reporter plasmids. Our studies will help to identify the importance of PTHrP for the growth and function of malignant prostate cells and elucidate the molecular mechanisms that underlie the regulation of PTHrP production in this malignancy. These studies should provide basic information about the molecular and cellular biology and clinically relevant information about the function of this polypeptide in human prostate cancer.
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