The overall objective of this work is a more refined understanding of hormone action in the ovary, with a particular focus on estrogen's specific regulation of cholesterol metabolism in granulosa cells. Studies during the first 3 years of this R01 grant have provided an excellent basis for a continuing emphasis on estrogen's control of the following key steps that regulate sterol utilization in ovarian cells: 1) De novo biosynthesis of cholesterol from acetyl coenzyme A, 2) The turnover of cellular cholesteryl ester stores, 3) The binding, internalization and degradation of lipoproteins, which carry cholesterol, and 4) The delivery of cholesterol to, and its utilization in, the cytochrome P-450 containing cholesterol side-chain cleavage reaction. The specific background developed during the first tenure of this grant will also permit a more exacting appraisal of the role of estrogen as a biological amplifier of hormone action in the ovary. In particular, we have recently demonstrated that estradiol interacts synergistically with certain potent ovarian effector hormones (e.g. FSH and pure somatomedin C). The mechanism(s) subserving estrogen's synergistic enhancement of progesterone biosynthetic capacity in granulosa cells will be examined in relation to each of the principal steps in cellular sterol metabolism defined by our specific aims (1) through (4). These new studies will utilize in part certain lipid research methods we have just developed and applied to investigating the actions of estrogen alone, and they will also invoke new and more refined techniques to elucidate precise changes in cholesterol disposal by granulosa cells. The time to develop these additional techniques has recently (Jan. 1985) been afforded under RCDA support. Consequently, we anticipate significantly extending available studies on the nature of the regulatory effects of estradiol and on the mechanisms subserving estradiol's biological amplification of hormone action in the ovary. Such knowledge will help to clarify the significant endocrine mechanisms that prepare granulosa cells for the high rates of progesterone biosynthesis ultimately required for normal steroidogenic function of the corpus luteum. Accordingly, these investigations are likely to contribute to new approaches to fertility regulation in the human, domestic animal or endangered wild species.
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