Race/Ethnicity/Immunity/Progesterone and Preterm Birth

早产（PTB）仍然是一个主要的公共卫生问题，使超过10%的分娩复杂化， 相关的围产期发病率和死亡率占总数的30%。最大的单一风险因素 PTB是既往PTB。早期和准确识别风险患者可能允许有针对性的干预措施。 尽管付出了巨大的努力，但美国的PTB率在过去30年中实际上有所增加。这一失败反映了一个贫穷的 对引发PTB的基本机制的理解，加上长期以来的假设，即早产 (PL)只是分娩时间不对从下生殖器上行感染是一个公认的 上尿路炎症机制，胎儿炎症反应综合征，蜕膜出血， 绒毛膜炎或其组合。然而，抗生素治疗未能降低PTB率。很可能 一旦下生殖道的先天免疫被破坏， 在上生殖道或胎儿室中建立炎症级联反应。我们 假设PTB反映了氧非依赖性（防御素和钙粒蛋白）和氧 依赖（氧自由基）防御机制的下部和上部生殖道， 某些种族中调节炎症级联反应的基因中某些多态性的隔离 这部分地解释了他们复发PTB的风险（具体目标1a）。我们假设女人注定 对于PTB表达宫颈阴道生物标志物，说明在PTB发生前几周或几个月先天免疫改变， PTB症状（宫颈成熟、早产宫缩或pPROM）的发作，可以可靠地 使用蛋白质组学工具鉴定（特定目的1b）。我们假设孕酮化合物 据报道，减少复发性PTB影响产妇下生殖道和上生殖道防御机制， 以及胎儿炎症反应轴（特异性目标2）。这份提案汇集了一位经验丰富的 一个多学科的团队，将在5年的时间内进行实验，测试这些假设的要素。

Preterm birth (PTB) remains a major public health problem, complicating >10% of all deliveries, and its associated perinatal morbidity and mortality represents 30% of the total. The greatest single risk factor for PTB is a prior PTB. Early and accurate identification of at risk patients may permit targeted interventions. Despite great effort, the US PTB rate has actually increased over the past 30y. This failure reflects a poor understanding of the basic mechanisms initiating PTB coupled to a long held assumption that preterm labor (PL) is simply term labor ill timed. Ascending infection from the lower genital is a well-recognized as a mechanism of upper tract inflammation, fetal inflammatory response syndrome, decidual hemorrhage, chorioamnionitis or combinations thereof. Yet, antibiotic therapy has failed to reduce the PTB rate. It is likely other therapeutic strategies are necessary once the innate immunity of the lower genital tract is overwhelmed and the inflammatory cascade established in the upper genital tract or fetal compartment. We hypothesize that PTB reflects an alteration of oxygen independent (defensins and calgranulins) and oxygen dependent (oxygen free radicals) defense mechanisms of the lower and upper genital tract, and that the sequestration of certain polymorphisms in genes regulating the inflammatory cascade among some ethnic groups accounts in part for their risk of recurrent PTB (Specific Aim 1a). We hypothesize women destined for PTB express cervicovaginal biomarkers illustrative of altered innate immunity weeks or months before onset of PTB symptoms (cervical ripening, preterm labor contractions or pPROM) that can be reliably identified using proteomic tools (Specific Aim 1b). We hypothesize that the progesterone compounds reported to decrease recurrent PTB affect maternal lower and upper genital tract defense mechanisms as well as the fetal inflammatory response axis (Specific Aim 2). This proposal brings together an experienced multidisciplinary team who will test elements of these hypotheses in experiments performed over a 5y period.