Race/Ethnicity/Immunity/Progesterone and Preterm Birth

种族/民族/免疫/黄体酮和早产

• 批准号: 6976904
• 负责人: CARL P WEINER
• 金额: $ 7.72万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6976904
• 关键词: African American; Hispanic Americans; biomarker; caucasian American; clinical research; cooperative study; defensins; enzyme linked immunosorbent assay; female; free radical oxygen; functional /structural genomics; genetic polymorphism; genetic susceptibility; human pregnant subject; immunogenetics; immunopharmacology; matrix assisted laser desorption ionization; pregnancy immunology; premature labor; progesterone; proteomics; racial /ethnic difference; surface enhanced laser desorption ionization; women' s health

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.

产品说明：早产（PTB）仍然是一个主要的公共卫生问题，其并发症占所有分娩的10%以上，其相关的围产期发病率和死亡率占总数的30%。PTB的最大单一风险因素是既往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。这一失败反映了对引发PTB的基本机制的认识不足，以及长期以来的假设，即早产（PL）只是时间不合适的足月分娩。来自下生殖器的上行感染是公认的上尿路炎症、胎儿炎症反应综合征、蜕膜出血、绒毛膜炎或其组合的机制。然而，抗生素治疗未能降低PTB率。一旦下生殖道的先天免疫被压倒，并且上生殖道或胎儿室中建立了炎症级联反应，则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（防御素和钙粒蛋白）和氧依赖性（氧自由基）防御机制的改变，并且在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部分地解释了他们复发PTB的风险（特异性目的1a）。我们假设，PTB患者在PTB症状（宫颈成熟、早产收缩或pPROM）发作前数周或数月表达宫颈阴道生物标志物，说明先天免疫改变，可以使用蛋白质组学工具可靠地识别（特异性目的1b）。我们假设，孕酮化合物报告减少复发性PTB影响产妇下，上生殖道防御机制，以及胎儿炎症反应轴（具体目标2）。该提案汇集了一个经验丰富的多学科团队，他们将在为期5年的实验中测试这些假设的要素。