In the ovary, steroid secretion is markedly episodic and is regulated, in part, by the levels of gonadotrophins, which in turn are regulated by the levels of ovarian hormones in a series of feedback loops, both positive and negative, the predictable pattern of changes in the levels of both gonadotrophins and steroids being known as the ovarian cycle. In this sense, therefore, ovarian steroidogenesis differs markedly from adrenal, testicular and placental steroidogenesis. The goal of this Competing Continuation Application is to understand the molecular basis for the regulation of steroidogenesis by the ovary; and in particular, for the unique episodic pattern of steroid hormone secretion characteristic of the ovarian cycle. In order to address this goal, we propose to establish the cis-regulatory and trans-acting elements responsible for the temporal and spatial expression of the genes encoding the enzymes responsible for cholesterol side-chain cleavage and 17 alpha hydroxylation, throughout the bovine and human ovarian cycles. The mechanisms whereby LH and FSH, acting via cyclic AMP, cause an increase in expression of these genes will also be investigated, as will the mechanisms whereby growth factors and cytokines, produced locally in the ovary, act in a paracrine and autocrine fashion to mediate the differential expression of these genes. These factors include epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factors alpha and beta (TGF-alpha and beta), insulin-like growth factor-I (IGF), and interleukin-beta (IL-1 beta). We will also seek to establish to what extent the temporal, tissue-specific expression of these genes in the various cell-types of the ovary, namely theca, granulosa and corpus luteum, is mediated by the actions of growth factors acting in both stimulatory and inhibitory fashions. Lastly, we will define the developmental regulation of steroidogenic enzymes in the bovine fetal ovary by establishing the cis-regulatory and trans-acting elements responsible for the switching on and off of expression of these steroidogenic enzymes during gestational development. Associated with the changes in steroidogenic gene expression are equally profound changes in the morphology of the cell types involved, as well as their organization, including vascularization of the developing corpus luteum. We submit that the mechanisms which regulate steroidogenic gene expression likely also regulate the expression of genes involved in the other aspects of ovarian differentiation, namely morphogenesis and angiogenesis; in other words, these are mechanisms which are fundamental to the processes of ovarian differentiation and development.
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