Thrombin-Stimulated Intrauterine Signaling Pathway

凝血酶刺激的宫内信号通路

基本信息

批准号：
7228973
负责人：
Mark Phillippe
金额：
$ 25.86万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2009-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Preterm delivery, which complicates 8-10% of pregnancies in the United States, results in significant neonatal and pediatric morbidity, and is responsible for about 75% of the neonatal mortality. The mechanisms underlying the onset of preterm labor are unclear; however, studies to date suggest that preterm delivery is often associated with genital tract infection, as suggested by elevated proinflammatory cytokines (e.g. IL2, ILa, TNF-a, and IFN-g). Although it has been shown that these cytokines lead to increased prostaglandin production by intrauterine tissues, it is unclear whether this is the only mechanism by which these pro-inflammatory cytokines lead to the stimulation of preterm contractions. The research described in this RO1 application will test the hypothesis: endotoxin (LPS) stimulates increased proinflammatory cytokines, especially IL-2, TNF-a and IFN-g resulting in activation of the "thrombin stimulated intrauterine signaling pathway"; i.e. enhanced phospholipid scramblase (PLS), tissue prothrombinase (Fgl2), prothrombin and thrombin receptor (PAR1) expression and activation leading to preterm contractions and delivery. Our preliminary studies have confirmed the molecular expression of all of the components of this pathway within the near term rat uterus. Using the LPS-induced preterm delivery model in the timed-pregnant rat, we will complete the following specific aims: 1) determine if Fgl2 expression and activation are increased in the preterm rat uterus, leading to prothrombinase activity, 2) determine if phospholipid scramblase expression and functional activity increase in the preterm rat uterus, leading to enhanced Fgl2 activity, 3) determine if increased intrauterine prothrombin expression occurs, leading to enhanced thrombin generation, 4) determine if uterine PAR-1 expression and activation are increased, leading to myometrial contractions, decidual necrosis, and intrauterine bleeding, and 5) test the hypothesis that the above phenomena occur in parallel and contribute to the role of prostaglandins during the events leading to LPS-stimulated preterm labor and delivery in the rat. These studies are anticipated to significantly improve our understanding of the mechanisms underlying preterm labor in the presence of intrauterine infection.

描述（由申请人提供）：早产，使美国8-10％的怀孕复杂化，导致了明显的新生儿和小儿发病率，并造成了约75％的新生儿死亡率。早产开始的机制尚不清楚。然而，迄今为止的研究表明，早产通常与生殖道感染有关，如促炎细胞因子（例如IL2，ILA，TNF-A和IFN-G）所暗示的那样。尽管已经表明，这些细胞因子会导致宫内组织产生前列腺素的增加，但尚不清楚这是否是这些促炎性细胞因子导致刺激早产收缩的唯一机制。 RO1应用中描述的研究将检验假设：内毒素（LPS）刺激促炎性细胞因子的增加，尤其是IL-2，TNF-A和IFN-G，从而激活了“凝血酶刺激肝素内信号通路”的激活”；即增强的磷脂cramblase（PL），组织凝血酶原酶（FGL2），凝血酶原和凝血酶受体（PAR1）表达和激活，导致早产收缩和分娩。我们的初步研究已经证实了该途径在近期大鼠子宫内的所有成分的分子表达。使用LPS诱导的早期大鼠中的LPS诱导的早产模型，我们将完成以下特定目的：1）确定早产大鼠子宫中FGL2表达和激活是否增加，导致凝血酶酶活性，2）确定磷酸化酶的表达和功能是否会增强FGL2的活性，3）是否会增强FGL2的活性，3）发生，导致凝血酶产生增强，4）确定子宫PAR-1表达和激活是否增加，导致肌层收缩，cant骨坏死和宫内出血，以及5）检验以下假说，即上述现象是在Prostaglandins在Prostaglandins of LPS促进的劳动和交付过程中的作用并有助于促进Prostagland的作用，并促进了Prestagland的作用。预计这些研究将显着提高我们对在宫内感染存在下早产的机制的理解。