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尚不清楚。我们的中心假设是，妊娠早期的滋养层细胞可以通过Toll样受体识别和响应病原体，滋养层细胞的这种先天免疫功能可能会影响妊娠结局。Toll样受体(Toll-like Receptor，TLR)是天然免疫系统的重要组成部分，识别微生物表面的保守序列，通过信号转导蛋白MyD88启动效应细胞功能。我们已经证明了妊娠早期滋养层细胞表达TLR-2和TLR-4。在被革兰氏阳性细菌组分连接后，TLR-2介导了妊娠早期滋养层细胞的凋亡。相反，由革兰氏阴性细菌组分连接TLR-4会诱导细胞因子的产生。因此，我们发现滋养层细胞可以通过两个不同的TLR对不同的细菌成分产生不同的反应。我们的目标是进一步确定TLR-2和TLR-4在早期妊娠滋养层细胞中的作用机制，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在早孕滋养层细胞中的作用机制 2.确定TLR-4在早孕滋养层细胞中的作用机制 3.检测早孕滋养层细胞对TLR表达的调节 4.体内TLR激活对妊娠的影响 关于滋养层细胞如何识别微生物并对其做出反应，人们知之甚少。妊娠中Toll样受体的区域是一个新的区域。因此，了解Toll样受体在正常胎盘中的作用是很重要的。这些研究将为滋养层细胞在感染存在时如何发挥作用提供新的见解，并将促进我们对病理情况的理解，如先兆子痫、胎儿宫内发育迟缓或早产。

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.