The long-term goals of the research activity in our laboratory are to understand the biochemical processes by which steroid and other hormones affect target organs and to provide molecular bases for clinical manipulation of the abnormal growth of these organs. Our goals in this research project are to determine the structures of delta4-3-ketosteroid-5alpha-oxidoreductase (5alpha-reductases) in liver, prostate and other organs of the rat and human and to study the mechanisms involved in the regulation of 5alpha-reductase gene expression in normal and abnormal male hormone-sensitive organs and cells.
The specific aims for the next five years are: I. Purification and amino acid sequence analysis of 5alpha- reductases. II. Preparation of polyclonal and monoclonal antibodies to 5alpha- reductases by immunization of animals and hybridoma techniques. III. Cloning of 5alpha-reductase cDNAs by using expression libraries, antibodies, affinity steroid binding, and specific oligonucleotide probes. IV. Structural analysis of 5alpha-reductases by determining nucleotide sequences of cloned cDNAs and deduced amino acid sequences of 5alpha-reductases. V. The use of cDNA and RNA probes, antibodies, in situ hybridization, nuclear run-off experiments, mRNA expression in oocytes, and cell transfection, in studies of 5alpha-reductase gene structures and the regulation of the expression of 5alpha- reductase genes in normal and abnormal target organs of androgens, such as prostate and skin. Studies from this project may provide new information and methods that are useful in the investigation of the regulatory mechanisms involved in the growth of androgen-sensitive organs and in the studies of molecular factors that can control 5alpha- dihydrotestosterone or 5alpha-reductase-linked androgen-insensitive syndromes, benign prostate hyperplasia, prostate cancers, acne, male-pattern baldness, and female hirsutism. Some of these biological systems will be investigated during this project period.
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