This is a renewal application aimed at elucidating some of the basic neuroendocrine and cellular mechanisms overning mammalian ovarian development. During the last period of support we employed a combination of cellular, molecular and genetic approaches to demonstrate the existence of a neurotrophin-mediated regulatory system that is acting at the interface between the endocrine and nervous systems -- contributes to the developmental control of ovarian function. In related studies, we identified a series of additional genes that may belong to the hierarchy of regulatory molecules controlling ovarian folliculogenesis, follicular growth and ovulation. The recognition of these new regulatory components, and the use of genetic approaches to modify the expression of genes in a cell-specific and temporally restricted manner, provides us with a new opportunity to unravel some of the key cell-cell regulatory mechanisms underlying mammalian ovarian development. To initiate this undertaking we propose two sets of studies: The first, to define the physiological importance of NGF and its receptors I follicular growth and ovulation, and their contribution to the etiology of ovarian cystic disease; the other, to elucidate the role that a set of functionally diverse genes found to be differentially expressed in the ovary at two key developmental phases (folliculogenesis and first ovulation) may play in the regulation of these processes. To this end, the following specific aims are proposed: 1. To test the hypothesis that, while required for normal follicular growth, NGF overproduction in endocrine cells of the follicular wall leads to the development of cystic ovarian disease via activation of the low-affinity neurotrophin receptor, p75NGFR. 2. To examine the hypothesis that activation of trkA, the high ffinity tyrosine kinase NGF receptor, in ovarian endocrine cells of mesenchymal origin contributes to the completion of two critical phases in the natural history of the developing ovary, the initiation of preantral follicular development and rupture of the follicular wall at ovulation. 3. To define the role that insulin receptor-related receptor (IRR), an orphan receptor of the insulin receptor family recently found to be co-expressed with trkA in thecal cells of periovulatory follicles, plays in ovulation, and to molecularly identify the gene encoding the IRR ligand. 4. To test the hypothesis that follicular formation requires the temporal and cell-specific coordinated expression of three functionally diverse genes found to be differentially displayed at the time of folliculogenesis; the adhesion molecule Cadherin-11, the protooncogene PTTG, and the transcriptional regulator ENX-1.
Showing the most recent 10 out of 61 publications
