This application seeks continued support for a long-standing research effort in basic reproductive biology. The central theme of the Program is signal transduction in reproductive tissues. Its objective is to elucidate fundamental mechanisms which will provide new insight into the diagnosis and treatment of infertility as well as the prevention of pregnancy. The participating investigators have each committed a significant effort to this endeavour and the Department of Obstetrics and Gynecology and the University of Pennsylvania Medical Center have allocated substantial space as well as supplemental monies to the Program in recognition of its importance. Five research projects are proposed, supported by an Administrative Core Unit and an Instrumentation core. Project 1, Hormonal regulation of uterine secretory protein (C.R. Lyttle, Responsible Investigator) focuses on the steroid hormone regulation of endometrial epithelial production of the third component of complement. The mechanisms by which estrogens, anti-estrogens and progestins modulate C3 gene expression and the function of C3 in the uterus will be explored. Project 2, Regulation of ovarian and placental steroidogenesis (J.F. Strauss, III, Responsible Investigator) deals with the regulation of intracellular cholesterol movement. The roles of two proteins (sterol carrier protein 2 and endozepine) in the movement of cholesterol to and within mitochondria will be examined. The mechanisms of action of these proteins and the ways in which their levels are regulated by tropic hormones will be defined. Project 3, Epididymal maturation of mammalian sperm (G. Gerton, Responsible Investigator) examines the maturation of sperm acrosomal proteins in the epididymis. The elements of the signalling system which leads to the maturation of two proteins, acrosin and acrogranin, will be defined. Project 4, Mechanisms of signal transduction in spermatozoa (G.S. Kopf, Responsible Investigator) will examine the role of G proteins in zona pellucida-activated sperm responses. The components of this novel signal transduction system will be characterized including the specific G proteins involved, their potential modification by phosphorylation and their involvement in triggering the rise in cyclic AMP which follows sperm binding to zonae. Project 5, Early reactions of fertilization in mouse (B.T. Storey, Responsible Investigator) aims at characterizing the 3- quinuclidinyl benzilate (QNB)-binding protein of sperm which appears to be a critical component in the mechanisms activating sperm upon binding to the zona pellucida. In addition, the dynamics of calcium in sperm will be characterized to establish the kinetics of change of this critical divalent cation during the initial stages of the fertilization process. The research projects are interrelated through the use of common cellular, biochemical and molecular methods, shared major equipment and the complimentary expertise of the participating investigators. This has enhanced productivity and stimulated the development of new avenues of research.
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