食物过敏是严重影响婴幼儿健康成长的重大医疗问题。我们已发表工作(Zhang et al, Sci Transl Med)表明CD14+单核细胞过强的炎症因子释放能力是诱发疾病的主要原因。但是导致单核细胞炎症应激能力升高的机制目前仍不明确。通过表观基因组和转录组筛选，近期预实验结果显示：食物过敏儿童单核细胞的苹果酸脱氢酶2（MDH2）的启动子发生了显著的去甲基化现象，MDH2表达增加，葡萄糖代谢通路活化。 那么，MDH2的启动子甲基化如何调控基因表达？ MDH2是否通过葡萄糖代谢调节炎症因子的分泌？我们将通过大量临床标本并结合MDH2功能抑制和基因敲除实验：（1）验证MDH2启动子甲基化与食物过敏的关系，（2）阐述启动子甲基化调控MDH2基因表达的机制，（3）明确MDH2调控炎症因子分泌的信号通路 。这将增加对婴幼儿过敏性疾病发病机制的了解，为疾病的早期预警和治疗提供新的分子标志物和靶标。

Hypersensitivity of the immune system to environmental agents such as pollen and food can cause allergic diseases, which collectively affect over one third of infants and children. We found CD14+ monocytes from cord blood of infants who developed food allergy secreted more inflammatory cytokines IL-1b, IL-6 and TNF-a upon stimulation with LPS, compared to those who did not develop food allergy. These inflammatory cytokines and the mucosal-derived cytokine TGF-b suppress IL-2 expression by CD4+ T cells, which promote the expression of large amount of IL-4 in T cells and lead to the development of IgE-mediated food allergy in children. To identify epigenetic mechanisms that govern immune deviation in the cord blood, we employed 450K methylation analysis on cord blood immune cells isolated from 5 food-allergic and 5 non-allergic infants. Promoter methylation at malate dehydrogenase 2 (MDH2) locus was significantly decreased in CD14+ monocytes in food-allergic infants. We hypothesize that promoter demethylation increases MDH2 expression and malate-aspartate shuttle (MAS), which in turn increases aerobic glycolysis, hypoxia-inducible factor (HIF1a) and inflammatory cytokine expression. We will: 1) validate whether MDH2 demethylation is a potential biomarker for food allergy, and 2) investigate whether MAS-HIF1a regulate inflammatory cytokine expression. This project will reveal potential novel early diagnostic biomarkers and mechanisms for allergic disease development in infants, and provide targets for therapy.