Maternal obesity and neonatal innate immunity

摘要 胎儿发育中的免疫系统对母体环境发出的信号极为敏感。 母亲孕前(孕前)肥胖最近已成为最显著的负面影响之一 后代免疫系统发育和成熟的调节者。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相关 炎症反应。更重要的是，最近的流行病学研究报告称，出生于 孕前体重指数高的母亲更容易患坏死性小肠结肠炎等严重感染 以及需要进入新生儿重症监护病房(NICU)的细菌性败血症。我们最近展示了 肥胖母亲所生婴儿的脐带血单核细胞产生了抑制的免疫反应 脂多糖(LPS)，提示Toll样受体(TLR)信号缺陷。这些观察结果提供了一个 肥胖母亲所生新生儿对严重感染的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。 明白了。该应用程序的目标是解决这一知识鸿沟。具体地说，我们将定义函数 孕前肥胖对新生儿单核细胞的影响及其机制 分子基础。此外，我们将把我们的实验数据与收集的临床参数联系起来 从怀孕的母亲以及婴儿出生时和在生命的第一年。这个应用程序的新颖性 在于系统生物学方法，它将基因组和功能读数与临床元数据相结合。 拟议实验的完成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为开发早期干预措施奠定基础。

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.