Race/Ethnicity/Immunity/Progesterone and Preterm Birth

描述：早产（PTB）仍然是一个主要的公共卫生问题，在所有分娩中占10%，其相关的围产期发病率和死亡率占总数的30%。PTB最大的单一危险因素是既往的PTB。早期和准确地识别高危患者可能允许有针对性的干预。尽管付出了巨大的努力，但在过去的30年里，美国的肺结核发病率实际上有所上升。这一失败反映了对启动PTB的基本机制的理解不足，以及长期以来认为早产（PL）只是不合时宜的足月劳动。下生殖器上行感染是公认的上生殖道炎症、胎儿炎症反应综合征、蜕膜出血、绒毛膜羊膜炎或其组合的一种机制。然而，抗生素治疗未能降低肺结核的发病率。一旦下生殖道的先天免疫被淹没，炎症级联在上生殖道或胎儿室建立，可能需要其他治疗策略。我们假设PTB反映了下生殖道和上生殖道的氧非依赖性（防御素和钙颗粒蛋白）和氧依赖性（氧自由基）防御机制的改变，并且在一些种族群体中，调节炎症级联的基因中某些多态性的隔离部分解释了他们复发PTB的风险（Specific Aim 1a）。我们假设患有PTB的女性在PTB症状（宫颈成熟、早产或pPROM）发作前几周或几个月就表达了表明先天免疫改变的宫颈阴道生物标志物，这些生物标志物可以用蛋白质组学工具可靠地识别出来（Specific Aim 1b）。我们假设，报道减少复发性肺结核的黄体酮化合物影响母体下生殖道和上生殖道防御机制以及胎儿炎症反应轴（Specific Aim 2）。该提案汇集了一个经验丰富的多学科团队，他们将在5年的时间里通过实验来检验这些假设的要素。

DESCRIPTION: 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.