The role and regulation of apoptosis during estrous cycle, embryo implantation and pregnancy

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Recognition and maintenance of pregnancy is a complex process involving both maternal and embryonic signals. Establishment of a communication between the conceptus (embryo and associated membranes) and the mother is a critical step for continuation of pregnancy. The failure to establish such a communication has been shown to be the most important cause of infertility among mammals. More than 80% of embryonic loss is due to malfunction during early pregnancy. In the human and rodents, fetally derived placental trophoblast cells come into close apposition with endometrial epithelium during early implantation processes where epithelial cells undergo apoptosis. At the same time, the lining endometrium transforms (decidualization) involving controlled proliferation and apoptosis of decidual cells. Although the importance of sex steroids (progesterone and estradiol) and transforming growth factor-b (TGF-b) in the regulation of implantation and decidualization processes is well established, how these regulators interact at the subcellular levels in determining the fate of endometrial cells is poorly understood and documented. While it is generally accepted that uterine cell death plays an important role during implantation and placentation, molecular mechanisms involved in triggering apoptosis processes in endometrial cells are unknown. Contrarily, in the absence of a conceptus in the uterus, the endometrium undergoes regression to allow formation of a new reproductive cycle. In the proposed research program, we plan also to investigate the importance of apoptosis during endometrial regression in a non fertile cycle. The overall objective of the proposed research program is to examine the endocrine, paracrine and autocrine regulation of apoptosis and cell survival during estrous cycle, embryo implantation and pregnancy. Information gained from these studies will help to understand the importance of apoptosis in these reproductive situations and will provide clues for specific cures to female infertility involving a malfunction at these levels. Moreover, these studies will form the basis for future investigations on the nature and regulation of various uterine endocrinopathies such as cervical and endometrial cancer.