Function of Toll-Like Receptors Throughout Gestation

描述（由申请人提供）：先天免疫系统是母胎界面的重要细胞组成部分，对胎儿的存活至关重要。我们的总体假设是先天免疫系统通过支持i)滋养细胞植入/侵袭，ii)血管形成和iii)宿主保护对正常妊娠是必要的。我们认为，植入部位的细胞成分通过细胞因子/趋化因子网络相互沟通。这种串扰通过被称为toll样受体（TLRs）的特定受体的表达发生，TLRs可能指导和协调细胞因子/趋化因子网络。我们的中心假设是，在植入和妊娠期间，在母胎界面表达的tlr作为对环境的识别和反应的传感器。我们的主要目标是确定和描述tlr在妊娠期间的具体作用。在这个项目申请中，来自耶鲁大学医学院妇产科和生殖科学部门的三组研究人员将评估tlr在滋养细胞、蜕膜细胞（基质/内皮细胞）和先天免疫细胞之间相互作用中的作用。此外，该项目将研究tlr在妊娠前三个月和足月期间滋养细胞侵袭、螺旋动脉转化和宿主保护中的作用。这三个小组在胎盘/子宫生物学和生殖免疫学方面有丰富的经验。在Project i中，（Mor/Abrahams）将验证滋养细胞通过tlr的表达对母体环境的反应来控制着床部位先天免疫系统的存在和功能的假设。项目二世。（Lockwood/Krikun）将验证个体间质和先天免疫细胞表达的TLRs的激活在促进滋养细胞侵袭和螺旋动脉转化中发挥作用的假设。项目第三。（Guller/Norwitz）将验证胎盘合体滋养细胞（SCT）和成纤维细胞（FIBs）中TLR和gr依赖信号通路之间的串扰可以保护胎儿免受微生物化合物的侵害，同时限制该部位的炎症。

DESCRIPTION (provided by applicant): The innate immune system represents an important cellular component at the maternal-fetal interface and it is critical for the survival of the fetus. Our overall hypothesis is that the innate immune system is necessary for normal pregnancy by supporting i) trophoblast implantation/invasion, ii) vascularization and iii) host protection. We propose that the cellular component at the implantation site communicate with each other throughout a network of cytokines/chemokines. Such crosstalk occurs through the expression of specific receptors, known as Toll-Like Receptors (TLRs), which may direct and coordinate this cytokine/chemokine network. Our central hypothesis is that TLRs expressed at the maternal-fetal interface serve as sensors for the recognition and response to the environment throughout implantation and gestation. Our main goal is to determine and characterize the specific role of TLRs during pregnancy. In this program application, three groups of investigators from the Department of Obstetrics, Gynecology and Reproductive Sciences at Yale University School of Medicine will evaluate the role of TLRs in the interactions between trophoblast cells, decidual cells (stromal/endothelial) and innate immune cells. Furthermore, the program will investigate the role of TLRs in, trophoblast invasion, spiral artery transformation and host protection during the first trimester of pregnancy and at term. The three groups have extensive experience in placental/uterine biology and reproductive immunology. In Project I. (Mor/Abrahams) will test the hypothesis that the trophoblast controls the presence and function of the innate immune system at the implantation site by responding to the maternal environment through the expression of TLRs. Project II. (Lockwood/Krikun) will test the hypothesis that the activation of TLRs expressed by decidual stromal and innate immune cells plays a role in promoting trophoblast invasion and transformation of spiral arteries. Project III. (Guller/Norwitz) will test the hypothesis that cross-talk between TLR and GR-dependent signaling pathways in placental syncytiotrophoblast (SCT) and fibroblasts (FIBs) protects the fetus against microbial compounds while limiting inflammation at this site.