The goal of this project is to further characterize the structure and expression of gonadal inhibins so that their role in the control of FSH synthesis and secretion can be more fully determined. Ovarian inhibin, or folliculostatin (FS), is a non-steroidal substance that preferentially suppresses the secretion of pituitary follicle-stimulating hormone (FSH). It is therefore important in the differential regulation of the pituitary gonadotropins FSH and LH, plays a role in the mammalian reproductive cycle, and has potential contraceptive properties. Inhibin is composed of two dissimilar subunits (A=18 kd, B=14 kd), the smaller of which exists in two forms (BA and BB) and can form a homo-dimer with FSH- releasing activity (FSH-releasing protein, FRP). We and others have isolated cDNA clones encoding one form of inhibin from porcine ovarian and human placental cDNA libraries. We now propose to isolate cDNA and genomic clones encoding the two subunits of rat ovarian inhibin/FRP, and to use these probes to examine in a sophisticated fashion the role of these hormones in the mammalian reproductive cycle. Specifically, pig inhibin cDNAs will be used to identify homologous rat inhibin cDNAs from a high complexity rat ovarian cDNA library, and DNA sequencing will be used to predict the complete structures of the rat inhibin-A and inhibin-B precursor proteins. The genes encoding the rat inhibin subunits will also be isolated and characterized. Inhibin-A and inhibin-B cDNA and genomic clones will be used for two basic purposes. Firstly, the cDNAs will be expressed in bacterial and mammalian cells to produce inhibin/FRP antibodies and proteins so that the physiological roles of inhibin/FRP in the rat can be determined. Secondly, inhibin cDNA and genomic probes will be used to study the expression and regulation of the rat inhibin-A and inhibin-B genes. The tissue- specificity and developmental timing of inhibin A-subunit and B- subunit gene expression will be determined, and changes in inhibin/FRP biosynthesis during the reproductive cycle and in response to hormonal stimuli will be investigated. In addition to contributing to our understanding of the control of FSH secretion, these studies may provide valuable insights into potential mechanisms of fertility regulation.
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