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

妊娠的识别和维持是一个涉及母体和胚胎信号的复杂过程。在受精卵（胚胎和相关膜）和母亲之间建立通信是延续妊娠的关键步骤。未能建立这种交流已被证明是哺乳动物不孕的最重要原因。超过80%的胚胎丢失是由于妊娠早期的功能障碍。在人类和啮齿类动物中，胚胎来源的胎盘滋养细胞在早期着床过程中与子宫内膜上皮密切相关，上皮细胞发生凋亡。同时，内膜转变（蜕细胞化）涉及蜕细胞增殖和凋亡的控制。尽管性类固醇（黄体酮和雌二醇）和转化生长因子-b （TGF-b）在子宫内膜着床和去个性化过程的调节中的重要性已经得到了很好的证实，但这些调节因子如何在亚细胞水平上相互作用，决定子宫内膜细胞的命运，尚不清楚和文献记载。虽然人们普遍认为子宫细胞死亡在着床和胎盘发生过程中起着重要作用，但子宫内膜细胞凋亡过程的分子机制尚不清楚。相反，在子宫内没有受孕的情况下，子宫内膜会退化以形成新的生殖周期。在我们提出的研究计划中，我们还计划研究细胞凋亡在非生育周期子宫内膜退化中的重要性。本研究的目的是研究发情周期、胚胎着床和妊娠期间内分泌、旁分泌和自分泌对细胞凋亡和细胞存活的调节。从这些研究中获得的信息将有助于理解细胞凋亡在这些生殖情况中的重要性，并将为涉及这些水平功能障碍的女性不孕症的具体治疗提供线索。此外，这些研究将为进一步研究宫颈癌和子宫内膜癌等各种子宫内分泌疾病的性质和调控奠定基础。

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.