Regulation of cell survival in the rat uterus

妊娠的识别、维持和终止是一个涉及母体和胚胎信号的复杂过程。在植入早期，啮齿动物子宫内膜上皮细胞发生凋亡。之后，基质细胞发生脱胞，随后发生基底蜕膜（decidua basalis， DB）退化，包括蜕膜细胞凋亡。在妊娠末期，严格控制前列腺素的分泌是诱导分娩所必需的。然而，调控子宫内膜细胞凋亡的分子机制尚未明确。有趣的是，我们的实验室已经表明，在大鼠怀孕期间，个体TGF-b异构体（TGF-b1、TGF-b2和TGF-b3）在子宫中的表达不同：TGF-b1和TGF-b2在植入和DB回归期间存在，而TGF-b3异构体仅在DB和分娩期间存在。我们还提供了证据表明，不同的TGF-b亚型可以激活子宫内膜细胞中不同的信号通路，因为只有TGF-b3可以诱导子宫内膜上皮细胞中Akt的磷酸化/激活。在怀孕的大鼠子宫中，多种TGF-b异构体经常共表达：不同的TGF-b异构体激活途径如何整合，并在怀孕子宫中改变细胞存活或细胞死亡的平衡，目前尚不清楚。本研究计划的总体和长期目标是研究和了解妊娠三个重要阶段(1)着床期、2)DB回归期和3)分娩期子宫内膜中TGF-b亚型的表达调控以及内分泌、旁分泌和自分泌活性。当前提案的短期目标是表征TGF-b亚型在以下方面的参与、作用机制和相互作用：(i)胚胎着床时子宫内膜上皮细胞死亡的调节，（ii）蜕膜DB期间基质细胞诱导的凋亡，以及（iii）分娩时前列腺素的调节和分泌。从这些研究中获得的信息将有助于了解TGF-b异构体在这些关键生殖状况中的重要性，并将为成功建立、维持和终止妊娠提供重要线索。

Recognition, maintenance and termination of pregnancy are complex processes involving both maternal and embryonic signals. In the rodents during early implantation, endometrial epithelial cells undergo apoptosis. Later, the stromal cells undergo decidualization, which is followed by decidua basalis (DB) regression, involving apoptosis of decidual cells. At the end of pregnancy, a tightly controlled production of prostaglandins is necessary to induce parturition. However, the molecular mechanisms governing endometrial cell apoptosis are not yet defined. Interestingly, our laboratory has showed that individual TGF-b isoforms (TGF-b1, TGF-b2 and TGF-b3) are differently expressed in the uterus during rat pregnancy: TGF-b1 and TGF-b2 are present during implantation and DB regression, whereas TGF-b3 isoform is only present during DB and parturition. We have also provided evidence that distinct TGF-b isoforms can activate distinct signaling pathways in endometrial cells, since only TGF-b3 induces phosphorylation/activation of Akt in endometrial epithelial cells. In the pregnant rat uterus, multiple TGF-b isoforms are often co-expressed: how distinct TGF-b isoform-activated pathways integrate, and shift the balance towards cell survival or cell death in the pregnant uterus, is poorly understood. The overall and long term objective of the proposed research program is to examine and understand the regulation of expression as well as the endocrine, paracrine and autocrine activity of the TGF-b isoforms in the endometrium during the three important phases of pregnancy: 1) implantation, 2) DB regression, and 3) parturition. The short term objectives of the current proposal are to characterize the involvement, the mechanisms of action and interactions of TGF-b isoforms in the (i) regulation of endometrial epithelial cell death at the time of embryo implantation, (ii) stromal cell-induced apoptosis during decidua DB and (iii) prostaglandins regulation and secretion at the time of parturition. Information gained from these studies will help to understand the importance of TGF-b isoforms during these critical reproductive situations and will provide important clues for successful establishment, maintenance and termination of pregnancy.