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.

产前叶酸状况可以预测一系列成人疾病的风险，包括心血管 疾病，肥胖和结肠癌，但驱动致病机制尚不清楚。这 拟议的工作将检验以下假设：母体叶酸状况计划风险 通过改变造血干细胞，在后代的整个生命周期中与炎症有关的疾病 （HSC）从开发开始的功能。叶酸介导的一种碳代谢提供 核苷酸生物合成和细胞甲基化反应的单碳碳的唯一来源。 由于饮食摄入量改变或常见的遗传多态性而导致的叶酸状况受损会影响 增殖，基因组稳定性，最著名的是表观遗传调节。鉴于成人HSC 功能会因表观遗传调节，代谢和DNA损伤的变化而改变，我们 假设叶酸状况的早期扰动会影响HSC的发展和 通过在胎儿发育过程中影响这些参数的功能。我们最近显示了 产前免疫扰动可以通过 产后影响HSC的组成和输出。在这里，我们将维护老鼠 在妊娠期间，叶酸（FA）缺乏或FA补充饮食，并测试 操纵叶酸状态在造血发育和成人HSC功能方面。在AIM 1中，我们 将确定母体叶酸状况对胎儿叶酸代谢，胎儿的直接影响 造血和胎儿HSC通过移植功能。在AIM 2中，我们将测试如何修改 产前期间的叶酸状况会影响造血和HSC功能成年。 我们的数据将提供有关早期生活条件计划的新信息HSC功能和 整个生命周期的输出。