Maternal obesity and neonatal innate immunity

母亲肥胖与新生儿先天免疫

• 批准号: 10489886
• 负责人: Ilhem Messaoudi
• 金额: $ 13.19万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10489886
• 关键词: Maternal; obesity; neonatal; innate; immunity

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.

概括 胎儿中发育的免疫系统对来自母校环境的信号极为敏感。 孕产妇怀孕（牙形）肥胖最近已成为最重要的负面之一 后代免疫系统开发和成熟的监管机构。动物模型的发现表明 孕妇高脂饮食诱导的肥胖与抗菌反应衰减和异常有关 炎症反应。更重要的是，最近的流行病学研究报告说， 怀孕前BMI高的母亲更容易受到严重感染的影响，例如坏死性小肠结肠炎 和激进的败血症，需要入院新生儿重症监护病房（NICU）。我们最近显示了 来自肥胖母亲出生的婴儿的脐带血单核细胞产生了对的免疫反应 脂多糖（LPS），指示了Toll样受体（TLR）信号缺陷。这些观察结果提供了 肥胖母亲出生的新生儿对严重感染的敏感性增加的潜在解释。 但是，在肥胖母亲的后代中减少宿主防御的基础机制仍然很差 理解。该应用程序的目的是解决此知识差距。具体来说，我们将定义功能 孕妇孕前肥胖引起的人类新生儿单核细胞的改变并发现它们 分子基础。此外，我们将将实验的数据与收集的临床参数联系起来 来自怀孕的母亲以及出生时的孩子，以及生命的第一年。这个应用的新颖性 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。 提出的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发现将构成发展早期干预措施的基础。