Innate Immune Responses of Trophoblasts in Pregnancy

描述（由申请人提供）：宫内感染和妊娠并发症之间的关系知之甚少。我们的中心假设是，早期妊娠滋养层细胞可以通过Toll样受体识别和应答病原体，滋养层细胞的先天免疫功能可能会影响妊娠结局。Toll样受体（TLR）是先天免疫系统的关键组分，其识别微生物表面上的保守序列并通过信号传导衔接蛋白MyD 88触发效应细胞功能。我们已经证明，早期妊娠滋养层细胞表达TLR-2和TLR-4。革兰氏阳性细菌成分连接后，TLR-2介导妊娠早期滋养层细胞凋亡。相反，TLR-4通过革兰氏阴性细菌组分的连接诱导细胞因子产生。因此，我们发现滋养层细胞可以通过两种不同的TLR对不同的细菌组分产生不同的反应。我们的目标是进一步表征TLR-2和TLR-4在妊娠早期滋养层细胞中发挥作用的机制，并确定它们在妊娠期间的作用。 我们的具体目标是： 1.确定TLR-2在妊娠早期滋养层细胞中发挥作用的机制 2.确定TLR-4在妊娠早期滋养层细胞中发挥作用的机制 3.通过早期妊娠滋养层细胞确定TLR表达的调节 4.确定TLR激活对体内妊娠的影响 关于滋养层细胞如何识别和响应微生物的知之甚少。Toll样受体在妊娠中的作用是一个新的领域。因此，了解Toll样受体在正常胎盘中的作用非常重要。这些研究将为滋养层细胞在感染情况下的功能提供新的见解，并将促进我们对病理条件的理解，如先兆子痫，IUGR或早产。

DESCRIPTION (provided by applicant): The relationship between intrauterine infections and complications of pregnancy is poorly understood. Our central hypothesis is that first trimester trophoblast cells can recognize and respond to pathogens through Toll-like receptors, and that such innate immune functions of trophoblast cells may influence pregnancy outcome. Toll-like receptors (TLR) are key components of the innate immune system which recognize conserved sequences on the surface of microorganisms and trigger effector cell functions via the signaling adapter protein, MyD88. We have demonstrated that first trimester trophoblast cells express TLR-2 and TLR-4. Following ligation by gram-positive bacterial components, TLR-2 mediates apoptosis in first trimester trophoblast cells. In contrast, ligation of TLR-4 by gram-negative bacterial components induces cytokine production. Thus, we have found that trophoblast cells can mount divergent responses to different bacterial components through two distinct TLR. Our objectives are to further characterize the mechanisms by which TLR-2 and TLR-4 function in first trimester trophoblast cells and to determine their role during pregnancy. Our specific aims are to: 1. Determine the mechanisms by which TLR-2 functions in first trimester trophoblast cells 2. Determine the mechanism by which TLR-4 functions in first trimester trophoblast cells 3. Determine the regulation of TLR expression by first trimester trophoblast cells 4. Determine the effects of TLR activation on pregnancy in vivo Little is known about how trophoblast cells recognize and respond to microorganisms. The area of Toll-like receptors in pregnancy is a novel one. Therefore, it is important to understand the role of Toll-like receptors within the normal placenta. These studies will provide new insight into how trophoblast cells function in the presence of an infection and will advance our understanding of pathological conditions, such as preeclampsia, IUGR or preterm deliveries.