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 胎儿正在发育的免疫系统对来自母体环境的信号极其敏感。 母亲孕前肥胖最近已成为最显着的负面影响之一 动物模型的研究结果表明，后代免疫系统发育和成熟的调节者。 母亲高脂肪饮食引起的肥胖与抗微生物反应减弱和异常有关 更重要的是，最近的流行病学研究报告称，新生儿出生时会出现炎症反应。 孕前BMI较高的母亲更容易患坏死性小肠结肠炎等严重感染 我们最近显示，需要入住新生儿重症监护病房 (NICU) 的细菌性败血症。 肥胖母亲所生婴儿的脐带血单核细胞会减弱免疫反应 脂多糖 (LPS)，Toll 样受体 (TLR) 信号传导缺陷的指标。这些观察结果提供了一个结果。 肥胖母亲所生的新生儿对严重感染的易感性增加的潜在解释。 然而，肥胖母亲的后代宿主防御能力下降的机制仍然很差 具体来说，我们将定义函数式。 母亲孕前肥胖引起的人类新生儿单核细胞的变化并揭示其变化 此外，我们会将实验数据与收集的临床参数联系起来。 来自怀孕的母亲以及孩子在出生时和生命第一年的时间 该应用程序的新颖性。 关键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。 完成所提出的实验将揭示导致新生儿的分子机制 单核细胞功能和我们的发现将构成制定早期干预措施的基础。