Innate Immune Responses of Trophoblasts in Pregnancy

描述（由申请人提供）：宫内感染与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滋养层细胞可以通过toll样受体识别病原体并对其作出反应，并且滋养层细胞的这种先天免疫功能可能影响妊娠结局。toll样受体（TLR）是先天免疫系统的关键组成部分，它识别微生物表面的保守序列，并通过信号转接器蛋白MyD88触发效应细胞功能。我们已经证明妊娠早期滋养细胞表达TLR-2和TLR-4。在革兰氏阳性细菌结扎后，TLR-2介导妊娠早期滋养细胞的凋亡。相反，通过革兰氏阴性细菌组分连接TLR-4诱导细胞因子的产生。因此，我们发现滋养细胞可以通过两种不同的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表征TLR-2和TLR-4在妊娠早期滋养细胞中的作用机制，并确定它们在妊娠期间的作用。

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.