Regulation of hematopoietic stem cell function by prenatal folate status

产前叶酸状态对造血干细胞功能的调节

• 批准号: 10373851
• 负责人: Anna E. Beaudin
• 金额: $ 23.68万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373851
• 关键词: Adult; Adult Children; Affect; Automobile Driving; Carbon; Cardiovascular Diseases; Cell Compartmentation; Cell Proliferation; Cell physiology; Chromatin; Clonal Expansion; Colon Carcinoma; DNA Damage; DNA Methylation; Data; Development; Developmental Process; Diet; Dietary intake; Disease; Epigenetic Process; Fetal Development; Folic Acid; Functional disorder; Gene Expression Regulation; Genetic Polymorphism; Genetic Transcription; Genome Stability; Goals; Health; Heart; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Histones; Immune; Impairment; Inflammation; Investigation; Knowledge; Life; Longevity; Lymphoid; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methylation; Modeling; Mus; Mutation; Neural Crest; Neural Tube Closure; Neural Tube Defects; Nucleotide Biosynthesis; Obesity; Onset of illness; Outcome; Output; Pathogenicity; Population; Pregnancy; Prenatal Nutrition; Prevention; Proteins; RNA; Reaction; Regulation; Risk; Shapes; Source; Stem Cell Development; Supplementation; Testing; Transplantation; Tube; United States; Work; adverse outcome; demethylation; disorder risk; epigenetic regulation; epigenomics; fetal; folic acid metabolism; folic acid supplementation; genome integrity; immune function; migration; novel; offspring; population health; postnatal; postnatal period; prenatal; prenatal testing; progenitor; programs; response; stem cell function

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.

产前叶酸状况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。这个 拟议的工作将检验以下假设：孕妇叶酸状况计划对 通过改变造血干细胞改变子代的一生中的炎症相关疾病 (HSC)从发展到现在的职能。叶酸介导的一碳代谢提供 核苷酸生物合成和细胞甲基化反应中一碳的唯一来源。 由于饮食摄入量改变或常见基因多态影响的叶酸状态受损 增殖、基因组稳定性，以及最值得注意的表观遗传调控。考虑到成年的HSC 功能因表观遗传调节、新陈代谢和DNA损伤的改变而改变 假设叶酸状态的早期扰动将影响HSC的发育和 在胎儿发育过程中通过影响这些参数发挥作用。我们最近展示了 产前免疫紊乱可以通过以下方式塑造长期的造血和免疫功能 出生后对HSCs的组成和产量均有影响。在这里，我们将保持老鼠在 叶酸(FA)缺乏或添加叶酸(FA)的饮食，并测试其对妊娠的影响 操纵叶酸状态对造血发育和成人HSC功能的影响。在目标1中，我们 将决定母亲叶酸状况对胎儿叶酸代谢的直接影响 通过移植促进造血和胎儿HSC的功能。在目标2中，我们将测试如何修改 胎儿期的叶酸状态会影响成年期的造血和HSC功能。 我们的数据将提供有关早期生命条件计划HSC如何发挥作用的新信息 在整个生命周期内的输出。