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。在胚胎(胚胎和相关的膜)和母亲之间建立沟通是继续怀孕的关键一步。未能建立这样的沟通已被证明是哺乳动物不育的最重要原因。超过80%的胚胎丢失是由于怀孕早期的功能障碍。在人类和啮齿类动物中，胎盘滋养层细胞在着床早期与子宫内膜上皮紧密结合，在此过程中上皮细胞发生凋亡。与此同时，衬里子宫内膜的转化(蜕膜化)涉及到蜕膜细胞的受控增殖和凋亡。虽然性激素(孕酮和雌二醇)和转化生长因子-b(TGF-b)在调控着床和蜕膜化过程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却鲜有了解和文献记载。虽然人们普遍认为子宫细胞死亡在着床和胎盘形成过程中起着重要的作用，但触发子宫内膜细胞凋亡过程的分子机制尚不清楚。相反，在子宫中没有胚胎的情况下，子宫内膜经历退化，以形成新的生殖周期。在拟议的研究计划中，我们还计划研究细胞凋亡在非生育周期中子宫内膜退化过程中的重要性。该研究计划的总体目标是研究动情周期、胚胎着床和妊娠过程中细胞凋亡和存活的内分泌、旁分泌和自分泌调节。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状况中的重要性，并将为涉及这些水平的功能障碍的女性不孕不育的具体治疗提供线索。此外，这些研究将为今后研究各种子宫内分泌疾病的性质和调控奠定基础，如宫颈癌和子宫内膜癌。

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.