Decidua and Fetal Membranes as a Paracrine System

描述(申请人提供)：早产不仅是婴儿死亡的主要原因，而且使幸存的个人面临严重的精神和身体残疾以及重大成人疾病的风险增加。早产胎膜早破(PPROM)占所有早产的30%-40%，其中约40%是由感染引起的。到目前为止，我们已经确定了PPROM唯一的非传染性途径。在这些没有感染的PPROM妇女中，蜕膜和胎盘中松弛素基因和蛋白的表达增加。松弛素通过刺激IGF-11和增加细胞外基质(ECM)的降解而促进胎儿胎膜的生长。 我们在罕见的胎膜早破组织中测量了488个基因，没有许多与早产相关的常见混杂变量，结果显示松弛素和其他29个基因的表达发生了变化。从这些数据中，选择了三组基因/基因途径进行进一步研究：一条发育/生长途径，一条炎症途径，以及两个其产物改变细胞外基质结构的基因。我们将把松弛素放在这些变化的背景下，以便进一步了解这一病理。因此，在特定的目标1中，我们将研究松弛蛋白与PPROM、细胞系、组织外植体和体内改变的基因/通路的关系。在具体目标2中，我们将使用恒河猴模型进行一项合作研究，并在早产时将松弛素直接注入羊膜腔。膜的结构和感兴趣的基因/途径将被研究。在具体目标3中，将使用体外模型来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。这些变化将在体内PPROM之后寻求。综合分析结果将显著提高我们对胎膜早破非感染性病因(S)的认识。

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.