Decidua and Fetal Membranes as a Paracrine System

描述（由申请人提供）：早产不仅是婴儿死亡的主要原因，而且使幸存者面临严重的精神和身体残疾以及主要成人疾病的风险增加。早产胎膜早破（PPROM）是30-40%早产的原因，其中约40%是由于感染。迄今为止，我们已经确定了PPROM的唯一非感染性途径。在这些患有PPROM且没有感染的妇女中，蜕膜和胎盘中松弛素基因和蛋白质的表达增加。松弛素通过刺激IGF-II和增加细胞外基质（ECM）的降解引起胎膜生长增加。 我们测量了罕见PPROM组织中的488个基因，没有许多与早产相关的常见混杂变量，并显示松弛素和其他29个基因的表达发生了改变。从这些数据中，已经选择了三组基因/基因途径进行进一步研究：发育/生长途径，炎症途径和两个基因，其产物改变ECM的结构。我们将把松弛素置于这些变化的背景下，以进一步了解这种病理学。因此，在特定目标1中，我们将研究松弛素与PPROM、细胞系、组织外植体和体内改变的基因/途径的关系。在具体目标2中，我们将使用恒河猴模型进行合作研究，并在早产时将松弛素直接注入羊膜腔。将研究膜的结构和感兴趣的基因/途径。在特定目标3中，将使用体外模型研究破裂对组织的影响。这将使我们能够区分PPROM的原因及其影响。然后将在PPROM体内后寻找这些变化。综合结果将显著增加我们对PPROM非感染性原因的理解。

DESCRIPTION (provided by applicant): Preterm birth is not only the major cause of infant mortality, but also places the surviving individual at increased risk for significant mental and physical disabilities and major adult diseases. The preterm premature rupture of the fetal membranes (PPROM) is the cause of 30-40% of all preterm births and about 40% of these are due to infection. We have identified the only non-infectious pathway for PPROM to date. In these women with PPROM and no infection, there is increased expression of the relaxin genes and proteins in the decidua and placenta. Relaxin causes increased growth of the fetal membranes via stimulation of IGF-ll and increased degradation of the extracellular matrix (ECM). We have measured 488 genes in rare PPROM tissues, devoid of many of the usual confounding variables associated with preterm birth and shown relaxin and the expression of 29 other genes altered. From these data, three sets of genes/gene pathways have been chosen for further study: a pathway for development/growth, an inflammatory pathway and two genes whose products alter the structure of the ECM. We will place relaxin into the context of these changes, in order to understand this pathology further. Thus, in Specific Aim 1, we will study the relationships of relaxin to the genes/pathways altered at PPROM, in cell lines, tissue explants and in vivo. In Specific Aim 2, we will carry out a collaborative study using a rhesus monkey model and give relaxin directly into the amniotic cavity at preterm. The structure of the membranes and the genes/pathways of interest will be studied. In Specific Aim 3, an in vitro model will be used to study the effects of the rupture on the tissue. This will allow us to distinguish the cause of PPROM from its effect. These changes will then be sought after PPROM in vivo. The combined results will significantly increase our understanding of the non-infectious cause(s) of PPROM.