Maternal obesity and neonatal innate immunity

总结 胎儿发育中的免疫系统对来自母体环境的信号极其敏感。 母亲怀孕前（pregravid）肥胖最近已成为一个最显着的负面影响， 后代免疫系统发育和成熟的调节因子。动物模型的研究结果表明， 母体高脂饮食诱导的肥胖与抗微生物反应减弱和异常的 炎症反应。更重要的是，最近的流行病学研究报告说， 孕前BMI高的母亲更容易患严重感染，如坏死性小肠结肠炎 以及需要进入新生儿重症监护室（NICU）的细菌性脓毒症。我们最近的研究表明 肥胖母亲所生婴儿的脐带血单核细胞会抑制免疫反应， 脂多糖（LPS），指示Toll样受体（TLR）信号传导缺陷。这些观察提供了一个 肥胖母亲所生新生儿对严重感染易感性增加的可能解释。 然而，肥胖母亲的后代宿主防御能力降低的机制仍然很差， 明白本应用程序的目标是解决这一知识差距。具体来说，我们将定义函数 孕妇孕前肥胖诱导的人类新生儿单核细胞的改变，并揭示其 分子基础此外，我们将把实验数据与收集的临床参数联系起来， 从怀孕的母亲以及出生时和出生后第一年的孩子身上。本申请的新奇 在于将基因组和功能读数与临床元数据相结合的系统生物学方法。 完成拟议的实验将揭示导致新生儿改变的分子机制。 单核细胞功能和我们的研究结果将形成发展早期干预的基础。

SUMMARY The developing immune system in the fetus is extremely sensitive to signals from the maternal environment. Maternal pre-pregnancy (pregravid) obesity has recently emerged as one of the most significant negative regulators of the offspring’s immune system development and maturation. Findings from animal models indicate maternal high fat diet-induced obesity is associated with dampened anti-microbial responses and aberrant inflammatory responses. More importantly, recent epidemiological studies have reported that neonates born to mothers with high pre-pregnancy BMI are more susceptible to severe infections such as necrotizing enterocolitis and bacterial sepsis requiring admission to the neonatal intensive care unit (NICU). We have recently shown that cord blood monocytes from babies born to obese mothers generated dampened immune responses to lipopolysaccharide (LPS), indicative of a Toll-like receptor (TLR) signaling defect. These observations provide a potential explanation for the increased susceptibility to severe infections in neonates born to obese mothers. However, the mechanisms underlying reduced host defense in offspring of obese mothers remain poorly understood. The goal of this application is to address this knowledge gap. Specically, we will define functional alterations in human neonatal monocytes induced by maternal pre-pregnancy obesity and uncover their molecular underpinnings. Moreover, we will link data from our experiments with clinical parameters collected from the pregnant mother as well as the child at birth and during the first year of life. The novelty of this application lies in the systems biology approach that integrates genomic and functional readouts with clinical metadata. Completion of the proposed experiments will reveal the molecular mechanisms that result in altered neonatal monocyte function and our findings will form a basis for developing early interventions.