Effects of Maternal Obesity on Offspring Immune System

项目总结/摘要 肥胖在美国已经达到了流行病的程度，最近的研究表明， 肥胖母亲的孩子比非肥胖母亲的孩子更容易肥胖。的 这种关联的解释尚不清楚。因为肥胖与广泛分布的巨噬细胞有关- 依赖性炎症状态，我们假设肥胖母亲的肥胖相关因素与 胎盘屏障，并对胎儿免疫系统产生不利影响。我们进一步假设单核细胞， 在发育中的胎儿中，免疫细胞构成了相当大的一部分，对这种免疫细胞特别敏感。 因素我们的初步数据支持这一概念，我们表明，在饮食诱导的胎儿单核细胞 肥胖小鼠的表型相对于非肥胖小鼠胎儿中的相同细胞发生了改变， 饮食.因此，在本提案中，在目标1中，我们将解释母体肥胖对发育的影响。 在表型、功能、表观遗传和转录水平上， 此外，我们将使用质谱仪结合我们的新支架算法来分析变化 单核细胞和其他主要免疫细胞群体在多个组织中的多个时间点， 正常小鼠和肥胖小鼠的后代。在目标2中，根据初步数据显示，高脂肪饮食喂养 雌性小鼠的胆固醇和脂肪酸水平增加，可以通过胎盘，我们将直接 测试这些因素对胎儿单核细胞功能的影响。待建议的研究完成后，我们会 已经确定了影响胎儿单核细胞和潜在的其他免疫细胞的母体因素，我们将 了解它们的影响在出生后是否持续。

Project Summary/Abstract Obesity has reached epidemic proportions in the U.S, and recent studies have demonstrated that the children of obese mothers are far more likely to become obese than the children of non-obese mothers. The explanation for this association is unknown. Since obesity is associated with a widespread macrophage- dependent inflammatory state, we hypothesize that obesity-associated factors in obese mothers cross the placental barrier and adversely affect the fetal immune system. We further hypothesize that monocytes, which constitute a substantial portion of immune cells in the developing fetus, are particularly sensitive to such factors. Our preliminary data support this concept; we show that monocytes in the fetuses of diet-induced obese mice are phenotypically altered relative to the same cells in the fetuses of non-obese mice fed a normal diet. Therefore, in this proposal, in Aim 1 we will decipher the effects of maternal obesity on developing monocytes in the liver and placenta at the phenotypic, functional, epigenetic and transcriptional levels. Additionally, we will use mass cytometry in combination with our novel Scaffolds algorithm to analyze changes of monocytes and other major immune cell populations in multiple tissues and at multiple time points in the offspring of normal versus obese mice. In Aim 2, based on preliminary data showing that high-fat diet fed female mice have increased levels of cholesterol and fatty acids, which can cross the placenta, we will directly test the effects of these factors on fetal monocyte function. Upon completion of the proposed studies, we will have identified maternal factors that affect fetal monocytes and potentially other immune cells, and we will learn if their effects persist after birth.