In the proposed period of support, we will extend our longstanding interest in the ovarian insulin-like growth factor (IGF) system to achieve a level of understanding sufficient to control this system in vivo. Thereafter, the concepts and possibly some of the compounds evaluated can be used to improve fertility in animals and ultimately women. The key to the projected advances is understanding the interface of the IGF-I system with the hormone and growth factor signals during early follicle development and the reproductive cycle. Two control points have been delineated: (1) The physiological control of IGF-I biosynthesis in granulosa cells. In this area, our systems have proven to be uniquely informative.
In Specific Aim 1, we will continue these studies to define in molecular terms the interaction of FSH and its cyclic AMP-dependent cascade on the IGF-I promoter. The demonstrated effect of other stimulators of this gene will be tracked to other promoter elements. To test these regulatory principles in vivo, expression IGF-I promoter transgenes will be tested in transgenic mice. (2) In Specific Aim 2, studies of the cell machinery which impacts on the IGF-I gene will be expanded to other aspects of ovarian cell function. The goal of this specific aim is to understand the interaction of IGF with FSH which demonstrably enhances granulosa cell replication, survival and differentiation at various times in the lifespan of the ovarian follicle. These studies will develop a detailed picture of the signal transduction pathways which mediate these effects.
Specific Aim 3 employs transgenic approaches to test the hypotheses derived from earlier descriptive studies and in vitro studies in Specific Aims 1 and 2 through transgenic approaches in vivo. The targets for control and investigation will include the local synthesis of IGF-I and IGF-I action mediated through its receptor and multiple points in the phosphorylation cascade which emanate from this receptor. Most of these studies have clinical relevance because inhibitors for the signal cascades to be examined are becoming widely available and because sufficient quantities of various IGF derivatives are now available to use in humans as a possible amplifying mechanism for ovulation. However, the series of experiments of most direct clinical relevance are those which seek to use conditional transgenic technology to build an insulin-resistant model of the polycystic ovarian syndrome. If successful, this model could open the door to critical evaluation, understanding, and treatment modalities.
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