Metabolic Programming of Hematopoietic Stem Cell Function by Prenatal Folate

产前叶酸对造血干细胞功能的代谢编程

• 批准号: 10752238
• 负责人: Brian Krum
• 金额: $ 4.22万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752238
• 关键词: Address; Adult; Adult Children; Affect; Automobile Driving; Bioinformatics; Biological Process; Blood; Carbon; Cell Compartmentation; Cell Lineage; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Cellular Metabolic Process; Chronic; Chronic Disease; Complex; Cytoplasm; Data; Data Set; Development; Developmental Process; Disease; Ensure; Epigenetic Process; Event; Exposure to; Failure; Fetal Development; Folic Acid; Folic Acid Deficiency; Formates; Gene Expression; Genome Stability; Glycolysis; Goals; Grant; Growth; Health; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Heterogeneity; Immune; Immune System Diseases; Inflammation; Intervention; Life; Link; Longevity; Lymphoid; Maps; Measures; Mediating; Membrane Potentials; Mentorship; Metabolic; Metabolism; Methylation; Mitochondria; Modeling; Molecular; Multipotent Stem Cells; Neural Tube Closure; Neural Tube Defects; Nutritional; Onset of illness; Outcome; Output; Oxidative Phosphorylation; Pathogenesis; Pattern; Population; Predisposition; Prevention; Process; Production; Proliferating; Public Health; Purines; Reactive Oxygen Species; Regulation; Research; Respiratory Chain; Risk; S-Adenosylhomocysteine; S-Adenosylmethionine; Shapes; Source; Stem Cell Development; Testing; Time; Toxicant exposure; Training; Translations; Universities; Utah; Work; Writing; career development; disorder risk; early-life nutrition; epigenetic regulation; fetal; folic acid supplementation; fortification; hematopoietic stem cell self-renewal; immune function; interest; mitochondrial membrane; mitochondrial metabolism; mother nutrition; nutrition; perinatal development; postnatal period; prenatal; prenatal testing; prevent; programs; self-renewal; skill acquisition; skills; stem cell function; stem cells; success; thymidylate; tool

ABSTRACT The goal of this project is to determine the effect of prenatal folate status on hematopoietic stem cell (HSC) establishment and function. The Developmental Origin of Health and Disease (DOHaD) hypothesis purports that many adult-onset diseases originate during perinatal development. This phenomenon of developmental programming of disease has since been demonstrated to be mediated at least in part by epigenetic changes during development, as these effects also occur trans-generationally. Folic acid is a major nutritional component that regulates cellular methylation and epigenetic patterning during fetal life, and prenatal folate deficiency is independently associated with failure of neural tube closure. Population-wide folic acid fortification is used in many parts of the world for the prevention of neural tube defects (NTDs), as approximately 70% of NTDs are prevented by folate supplementation. We will test the hypothesis that varying prenatal folate status programs risk for adult-onset disease by altering hematopoietic stem cell function and consequent immune trajectory from the developmental stage onwards. In this grant we propose that heterogeneity, function, and output of the adult HSC compartment can be shaped by perturbation during early development. Our previous work on the effects prenatal inflammation on the developing hematopoietic system show evidence that perturbation during early development can influence adult hematopoiesis and immune function. We will then apply this idea to test the effects of varying prenatal folate on hematopoietic establishment. Proliferation, genomic stability, and cell methylation are all processes influenced by folate-mediated OCM and are known to impact HSC establishment and function. We believe that early life alterations in folate-mediated OCM are likely to influence long-term HSC function. The underlying question of how maternal nutrition influences stem cell outcomes is underexplored. Our preliminary data shows that exposure to varying prenatal folate results in alterations in HSC establishment. Additionally, our model of prenatal folate metabolically reprograms HSCs during fetal life that persist into adulthood with altered function. These changes are in part driven by differences in metabolic gene expression. By examining how prenatal folate alters HSC function, we will be one of the first labs to directly identify the effects of maternal nutrition on health consequences by affecting the establishment and function of HSCs. In addition to the research statement contained within, I have developed a training plan that I believe will ensure my success across all aspects of the proposed research plan. The training plan I have developed not only addresses the training needs that are specific to this proposal but also builds on my interests that will give me tools to investigate metabolic programming, integrate “omics” datasets and stitch together multiple fields related to public health. This training plan includes training specific to metabolism and bioinformatic analysis, as well as career development skills such as mentorship focus, writing skills and presentation skills and academic professionalism. All of the research contained in this proposal will take place in the Beaudin Lab at the University of Utah.

摘要 该项目的目标是确定产前叶酸状态对造血干细胞(Hsc)的影响。 设立和运作。健康与疾病的发育起源(DOHAD)假说声称 许多成人发病的疾病起源于围产期的发育。这种发展的现象 自那以后，疾病的编程已被证明至少部分是由表观遗传变化所调节的 在发育过程中，因为这些影响也会跨代发生。叶酸是一种主要的营养成分 在胎儿时期调节细胞甲基化和表观遗传模式，而产前叶酸缺乏症 与神经管关闭失败独立相关。全人口范围的叶酸强化用于 世界上许多地区用于预防神经管缺陷(NTDS)，大约70%的NTDS是 通过补充叶酸来预防。我们将检验不同的产前叶酸状况计划的假设 通过改变造血干细胞功能和由此产生的免疫轨迹来增加成人发病的风险 以后的发展阶段。在这项资助中，我们提出了成虫的异质性、功能和输出 在早期发育过程中，可以通过扰动来形成HSC隔室。我们之前在效果方面的工作 发育中的造血系统的产前炎症表明，早期的扰动 发育会影响成人的造血和免疫功能。然后我们将应用这个想法来测试 产前不同叶酸水平对造血系统的影响。增殖、基因组稳定性和细胞 甲基化是受叶酸介导的OCM影响的所有过程，并已知影响HSC的建立 和功能。我们认为叶酸介导的OCM的早期生活改变可能会影响长期的HSC 功能。母体营养如何影响干细胞结果的根本问题还没有得到充分的探讨。我们的 初步数据显示，产前暴露于不同的叶酸会导致HSC建立的改变。 此外，我们的产前叶酸模型在胎儿期间对HSCs进行代谢重新编程，持续到 功能改变的成年期。这些变化在一定程度上是由代谢基因表达的差异推动的。 通过研究产前叶酸如何改变HSC的功能，我们将成为第一个直接确定其影响的实验室之一 通过影响肝星状细胞的建立和功能，产妇营养对健康后果的影响。除了……之外 我已经制定了一项培训计划，我相信这项计划将确保我的成功 涉及拟议研究计划的所有方面。我制定的培训计划不仅解决了 针对此提案的培训需求，但也建立在我的兴趣基础上，这将使我有工具进行调查 新陈代谢规划，整合“组学”数据集，并将与公共卫生相关的多个领域缝合在一起。 该培训计划包括针对新陈代谢和生物信息学分析以及职业生涯的培训 发展技能，如专注于指导、写作技能和演示技能以及学术专业性。 该提案中包含的所有研究都将在犹他大学的博丁实验室进行。