Regulation of hematopoietic stem cell function by prenatal folate status

产前叶酸水平可预测一系列成人疾病的风险，包括心血管疾病 疾病、肥胖和结肠癌，但驱动致病机制尚不清楚。的 拟议的工作将测试这一假设，即母亲的叶酸水平程序的风险， 通过改变造血干细胞在后代的整个生命周期中与炎症相关的疾病 (HSC)从发展开始。叶酸介导的一碳代谢提供了 核苷酸生物合成和细胞甲基化反应的唯一碳源。 由于饮食摄入量改变或常见遗传多态性影响而导致叶酸水平受损 增殖、基因组稳定性，以及最显著的表观遗传调节。考虑到成年HSC 由于表观遗传调节、代谢和DNA损伤的变化， 假设叶酸状态早期扰动将影响HSC的发育， 通过影响这些参数在胎儿发育过程中发挥作用。我们最近的研究表明 产前免疫扰动可以通过以下方式形成长期造血和免疫功能 影响生后HSC的组成和产量。在这里，我们将保持小鼠 叶酸（FA）缺乏或补充FA的饮食，并测试的影响， 操纵叶酸状态对造血发育和成体HSC功能的影响。目标1： 将决定母体叶酸状态对胎儿叶酸代谢的直接影响， 造血和胎儿HSC功能。在目标2中，我们将测试如何修改 胎儿期的叶酸状态影响造血和HSC功能直至成年。 我们的数据将提供关于早期生活条件如何编程HSC功能的新信息， 整个生命周期的输出。

Prenatal folate status predicts risk for a range of adult diseases, including cardiovascular disease, obesity, and colon cancer, but the driving pathogenic mechanisms are unknown. The proposed work will test the hypothesis that maternal folate status programs risk for inflammation-related disease across the lifespan in offspring by altering hematopoietic stem cell (HSC) function from development onwards. Folate-mediated one carbon metabolism provides the sole source of one-carbons for nucleotide biosynthesis and cellular methylation reactions. Impaired folate status due to altered dietary intake or common genetic polymorphisms affects proliferation, genomic stability, and, most notably, epigenetic regulation. Given that adult HSC function is altered by changes in epigenetic regulation, metabolism, and DNA damage, we hypothesize that early perturbations in folate status will influence HSC development and function by influencing these parameters during fetal development. We have recently shown that prenatal immune perturbation can shape long-term hematopoiesis and immune function by influencing both the composition and output of HSCs postnatally. Here, we will maintain mice on folic acid (FA) deficient or FA-supplemented diet throughout gestation, and test the effects of manipulating folate status on hematopoietic development and adult HSC function. In Aim 1, we will determine the immediate impact of maternal folate status on fetal folate metabolism, fetal hematopoiesis, and fetal HSC function by transplantation. In Aim 2, we will test how modified folate status in the prenatal period influences hematopoiesis and HSC function into adulthood. Our data will provide novel information on how early life conditions program HSC function and output across the lifespan.