The overall objective of this proposal is to understand the mechanism by which gonadotropin regulates progesterone biosynthesis by the rat corpus luteum. Gonadotropin action may be broadly looked upon as acting in two different ways. The acute effect involves regulation of steroidogenesis acting through processes that lead to an increased availability of steroid substrates. This leads to increased steroidogenesis by facilitating substrate movement to the inner mitochondrial membrane where cholesterol side chain cleavage enzyme is localized. The chronic effect of gonadotropins would lead to an increase in the steroidogenic enzyme(s). The major focus of the present proposal is to examine the acute regulation of steroidogenesis.
Four specific aims, each based on observations made during the current project period, are proposed.
AIM 1. What is the relative contribution of different pathways for cholesterol delivery in luteal cells and how do gonadotropins regulate these processes? This aim concerns the determination of cholesterol uptake from HDL by receptor-mediated and non- receptor mediated processes. Cholesterol needed for steroidogenesis is provided by circulating plasma lipoproteins. Since high density lipoprotein (HDL) is the major circulating lipoprotein in the rat, the uptake of cholesterol from HDL will be examined.
AIM 2. How is the cholesterol movement regulated in the luteal cell? This aim is intended to examine the regulation of HDL receptor by intracellular cholesterol concentration and the role of sterol carrier proteins (SCP2) in the transfer of cholesterol from cytosol to mitochondria.
AIM 3. Does IGF1 regulate luteal cell function synergistically with hCG in the rat? This concerns the examination of IGF-1 receptors by ligand binding and IGF-I receptor mRNA levels in luteal cells during pregnancy and the regulation of IGF-I receptors in luteal cells.
AIM 4. How does modification of purified hCG receptor affect the receptor function? This aim will be achieved by reconstitution of he enzymatically modified hCG receptor in phospholipid vesicles and fusion of these vesicles in Y-1 adrenal tumor cells to examine the effect of receptor modification on ligand binding and hCG responsive cyclic AMP production. The studies proposed address questions that have not been answered in any other system, so should provide new information.
Showing the most recent 10 out of 44 publications
