STRESS BIOLOGY, RACE/ETHNICITY & INFECTION IN PREGNANCY

描述(由申请人提供)：细菌性阴道病(BV)是妊娠期间最常见的生殖道感染，与早产风险增加有关。BV和感染相关早产的易感性的决定因素还不是很清楚。此外，BV感染率和Sequella的种族/民族差异的原因在很大程度上尚不清楚。我们提出了一个生物行为框架来研究这些问题，中心假设是产前应激作为一种生物结构，增加了感染BV的易感性，并加强了其病理生理后果。我们主要关注母体-胎盘-胎儿内分泌和免疫炎症过程，因为这两个系统都在调节感染易感性方面发挥关键作用，参与足月和早产的生理学和病理生理学，并且对应激反应高度敏感。我们建议对900名非裔美国人、西班牙裔和非西班牙裔白人孕妇进行纵向队列研究，以评估妊娠早期和中期两个时间点BV的患病率，量化每个时间点的内分泌和免疫炎症环境，测量已知与BV感染相关的行为，并跟踪受试者整个分娩过程。BV状态将通过革兰氏染色阴道涂片进行评估。内分泌应激参数将通过皮质醇、促肾上腺皮质激素释放激素(CRH)和雌三醇(E3)的测量来评估。采用体外全血组织培养系统，从细胞因子IL-1、IL-6、TNFα、IL-10和IL-12对细菌内毒素(LPS)刺激的反应来量化免疫炎症过程。我们的具体目标是：(1)内分泌应激生理学在增加妊娠期细菌性阴道病(BV)易感性中的作用，以及免疫抑制作为这一效应的介体的作用；(2)内分泌应激生理学在增加BV+妇女自然早产易感性中的作用，以及促炎免疫反应作为这一效应的介体的作用；以及(3)与压力有关的内分泌和免疫过程在多大程度上造成感染和感染相关早产发病率的种族/族裔差异这一建议的科学意义在于阐明决定怀孕期间发生生殖道感染及其不利后果(早产)的易感性或易损性的生物学机制，并澄清所观察到的种族/族裔对这些结果影响的生理基础。这一建议的实际意义是开发和评估新的方法(例如，体外免疫挑战方法)，以确定感染风险和感染相关早产风险较高的妇女，从而改进产科风险评估。

DESCRIPTION (provided by applicant): Bacterial vaginosis (BV), the most common reproductive tract infection in pregnancy, is associated with an increased risk for preterm birth. The determinants of susceptibility for developing BV and infection-related preterm birth are not well understood. Moreover, the causes of racial/ethnic differences in the prevalence and sequella of BV are largely unexplained. We propose a biobehavioral framework to study these issues, with the central hypothesis that prenatal stress, operationalized as a biological construct, heightens susceptibility for acquiring BV and potentiates its pathophysiological consequences. We focus on the maternal-placental-fetal endocrine and immune-inflammatory processes as the primary mechanisms of interest because both systems play a critical role in regulating susceptibility to infection, participate in the physiology and pathophysiology of term and preterm parturition, and are highly responsive to stress. We propose a longitudinal, cohort study of 900 African-American, Hispanic and nonHispanic White pregnant women to assess the prevalence of BV at two time points during early and mid gestation, quantify the endocrine and immune-inflammatory milieu at each of these times, measure behaviors known to be associated with the acquisition of BV, and follow subjects through delivery. BV status will be assessed by Gram stained vaginal smears. Endocrine stress parameters will be assessed by measures of cortisol, corticotropin-releasing hormone (CRH), and estriol (E3). Immune-inflammatory process will be quantified from responses of the cytokines interleukin (IL)-1, IL-6, TNFalpha, IL-10 and IL-12 to bacterial endotoxin (LPS) challenge using ex-vivo whole blood tissue culture system. Our specific aims are to examine: (1) the role of endocrine stress physiology in increasing susceptibility to developing bacterial vaginosis (BV) in pregnancy, and the role of immunosuppression as a mediator of this effect; (2) the role of endocrine stress physiology in increasing the susceptibility of BV+ women for spontaneous preterm birth, and the role of pro-inflammatory immune responses as a mediator of this effect; and (3) the extent to which stress-related endocrine and immune processes account for racial/ethnic disparities in prevalence of infection and infection-related preterm birth The scientific significance of this proposal pertains to elucidating biological mechanisms that determine susceptibility or vulnerability for developing reproductive tract infection in pregnancy and its adverse consequences (preterm birth), and clarifying the physiological basis for the observed effects of race/ethnicity on these outcomes. The practical significance of this proposal is the development and assessment of new ways (e.g., the ex-vivo immune challenge methodology) to identify women who are at heightened risk for infection and infection-related preterm birth, thereby improving obstetric risk assessment.