Dysregulation of maternal immunity during pregnancy by pregravid obesity

成功的怀孕需要免疫系统的精心协调的变化，以促进胎盘形成， 促进胎儿耐受和生长，引产。偏离这种严格管制的“怀孕 免疫钟”可能导致先兆子痫和分娩并发症。肥胖率在 育龄期妇女以惊人的速度增加，成为最常见的合并症之一 孕期之前发表的研究和我们的初步数据表明单核细胞的增强 重要的是，我们的初步分析表明， 母体妊娠前体重指数（BMI）>30消除了这种妊娠相关的单核细胞活化。这 观察结果为感染易感性增加和伤口愈合不良提供了可能的解释 肥胖孕妇中观察到的结果。我们假设慢性低度炎症 妊娠前肥胖诱导的单核细胞活化破坏了孕龄依赖性单核细胞活化， 免疫耐受表型。此外，考虑到蜕膜中的巨噬细胞是从 循环单核细胞，我们将研究肥胖对蜕膜细胞表型和功能的影响。 巨噬细胞我们进一步假设妊娠前肥胖导致高炎症表型 在蜕膜巨噬细胞内。我们将采用多维度的方法来测试这些假设。的 本申请的新奇在于系统生物学方法，其整合了表型、功能和 在外周血中和足月时在胎盘中的纵向基因组读数。完成建议 实验将揭示解释单核细胞活化过程中渐进性变化的分子机制， 健康怀孕的过程，以及肥胖是如何破坏的。

Successful pregnancy requires carefully coordinated changes in the immune system that facilitate placentation, promote fetal tolerance and growth, and induce labor. Deviations from this tightly regulated “pregnancy immunological clock” can lead to as pre-eclampsia and complications during labor. The rates of obesity amongst women of childbearing age have increased at an alarming rate, making it one of the most common comorbidities during pregnancy. Previously published studies and our preliminary data indicate an enhancement of monocyte response to LPS between 12 and 37 weeks of gestation Importantly, our preliminary analyses indicate that maternal pregravid body mass index (BMI) >30 abrogates this pregnancy-associated monocyte activation. This observation provides a potential explanation for the increased susceptibility to infections and poor wound healing outcomes observed in obese pregnant women. We hypothesize that chronic low grade inflammation induced by pregravid obesity disrupts the gestational age dependent monocyte activation, skewing them to an immunotolerant phenotype. Additionally, given that macrophages in the decidua are recruited from circulating monocytes, we will investigate the burden of obesity on phenotype and function of decidual macrophages. We further hypothesize that pregravid obesity results in a hyper-inflammatory phenotype within decidual macrophages. We will employ a multi-dimensional approach to test these hypotheses. The novelty of this application lies in the systems biology approach that integrates phenotypic, functional, and genomic readouts longitudinally in peripheral blood and at term in the placenta. Completion of the proposed experiments will reveal the molecular mechanisms that explain progressive changes in monocyte activation over the course of healthy pregnancy, and how that is disrupted with obesity.