Maternal temperament, stress, and inflammation in preterm birth

描述（由申请人提供）：早产是一个主要的公共卫生负担，仍然是全球新生儿发病率和死亡率的主要原因。我们的长期目标是确定扰乱正常分娩时间并导致早产的机制。许多因素影响早产的可能性，如细菌感染/定植、母体压力和遗传易感性。虽然这些因素增加了早产的频率，但大多数有这些因素的妇女都能足月分娩。在这项提案中，我们将测试一个新的假设-类似于癌症生物学中已经建立的见解-为了表现出早产，需要多个有害的“打击”一起作用。人类的观察性研究不可能证明这一点，因为许多不可控的变量混淆了因果关系。我们将利用一个非人类灵长类动物（恒河猴）模型系统，与典型的非灵长类动物系统相比，妊娠特征更类似于人类，以确定压力和感染是否相互作用，以促进早期劳动和分娩。我们认为，个人气质、炎症和压力将各自提供一个附加的“打击”，其中两个或更多的将是必需的 提前终止妊娠我们将检验以下具体假设：（1）母体应激和炎症协同作用导致早产;（2）个体对心理应激的易感性在早产的诱导中起关键作用;和（3）母体外周血或羊水激素和炎性反应在IL-10之前和之后将不同。1.怀孕期间的管理取决于潜在的气质和暴露于慢性压力。为了验证这些假设，我们的特定目标将确定：（1）母亲压力，炎症和个体易感性之间的相互作用，由于焦虑的气质，在早产恒河猴。(2)母亲的气质和压力对母亲的免疫力和激素的相互作用之前和之后的炎症挑战。(3)炎症刺激前后母体气质和慢性应激对羊水细胞因子、胰高血糖素和微生物群落结构的影响我们的跨学科团队将整合妊娠生理学，免疫学/炎症，灵长类动物行为/心理学，应激神经生物学，生物统计学和微生物组的专业知识，以更全面地研究增加早产风险的异质性途径，并对早产预防的因果机制和途径产生重要的新见解。

DESCRIPTION (provided by applicant): Preterm birth is a major public health burden that remains the leading cause of neonatal morbidity and mortality worldwide. Our long-term goal is to determine the mechanisms that disrupt the normal timing for parturition and lead to preterm birth. Numerous factors influence the likelihood of preterm birth, such as bacterial infection/colonization, maternal stress, and genetic predisposition. While these factors increase the frequency of preterm birth, the majority of women with these factors in isolation deliver at term. In this proposal, we will test a new hypothesis - similar to insights that have been established in cancer biology - that to manifest a preterm delivery, multiple detrimental "hits" acting together are required. Proving that this is the case is not possible with observational studies in humans, with many uncontrollable variables confounding causal relationships. We will exploit a non-human primate (rhesus) model system, with pregnancy characteristics more similar to humans than typical non-primate systems, to determine whether stress and infection interact to promote early labor and delivery. We propose that individual temperament, inflammation, and stress will each provide an additive "hit", of which two or more will be required to end pregnancy prematurely. We will test the specific hypotheses that: (1) maternal stress and inflammation synergize to induce preterm birth; (2) the individual susceptibility to psychological stressors plays a key role in the induction of preterm birth; and (3) maternal peripheral blood or amniotic fluid hormones and inflammatory responses will differ prior to and following IL-1 � administration during pregnancy depending on underlying temperament and exposure to chronic stress. To test these hypotheses, our Specific Aims will determine: (1) The interactions between maternal stress, inflammation, and the influence of individual susceptibility due to anxious temperament, in preterm birth in rhesus macaques. (2) The interactions of maternal temperament and stress on maternal immunity and hormones before and after an inflammatory challenge. (3) The effects of maternal temperament and chronic stress on amniotic fluid cytokines, prostaglandins and microbial community structure before and after an inflammatory challenge. Our transdisciplinary team will integrate expertise in the physiology of pregnancy, immunology/inflammation, primate behavior/psychology, the neurobiology of stress, biostatistics and the microbiome to more comprehensively investigate the heterogeneous pathways increasing preterm birth risk and yield important new insights into causal mechanisms and avenues for prematurity prevention.