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10%的分娩复杂化，其 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是先前的PTB。及早准确地识别高危患者可以进行有针对性的干预。 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。这一失败反映了一个糟糕的 对引发肺结核的基本机制的理解与早产的长期假设相结合 (PL)只是不合时宜的临产。从下生殖器向上感染是一种公认的 上尿路炎症机制，胎儿炎症反应综合征，蜕膜出血， 绒毛膜羊膜炎或其组合。然而，抗生素治疗并未降低肺结核的发病率。很有可能 一旦下生殖道的先天免疫功能丧失，就需要采取其他治疗策略。 不堪重负，炎症级联形成在上生殖道或胎儿隔室。我们 假设PTB反映了氧非依赖性(防御素和钙粒蛋白)和氧的变化 依赖(氧自由基)的下生殖道和上生殖道的防御机制，以及 某些民族间炎症级联调控基因的某些多态性的隔离 小组成员的部分原因是他们复发肺结核的风险(具体目标1a)。我们假设女人注定要 对于肺结核，在数周或数月前表达宫颈阴道生物标记物，说明先天免疫改变 可以可靠地出现肺结核症状(宫颈成熟、早产或胎膜早剥) 使用蛋白质组学工具进行鉴定(特定目标1b)。我们假设黄体酮化合物 报告称，减少复发肺结核影响产妇下、上生殖道防御机制如下 以及胎儿炎症反应轴(特异性目标2)。这项建议汇集了一位经验丰富的 多学科团队，将在为期5年的实验中测试这些假设的元素。

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.