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.

抽象的 该项目的目的是确定产前叶酸状况对造血干细胞的影响（HSC） 建立和功能。健康与疾病（DOHAD）假设的发展起源表明 许多成年疾病起源于围产期发育。这种发展现象 此后，疾病的编程至少部分是由表观遗传变化介导的 在开发过程中，由于这些效应也发生了经跨代的发生。叶酸是主要的营养成分 调节胎儿寿命期间的细胞甲基化和表观遗传模式，产前叶酸缺乏症是 与神经管闭合的失败独立相关。种群范围的叶酸强化用于 世界许多地方都预防神经管缺陷（NTD），因为大约70％的NTD是 通过补充叶酸阻止。我们将检验以下假设：不同的产前叶酸状态计划 通过改变造血干细胞功能的风险，可能 发展阶段。在这笔赠款中，我们建议成人的异质性，功能和产出 在早期开发过程中，HSC隔室可以通过扰动来塑造。我们以前关于效果的工作 发育中的造血系统对产前炎症表明，早期扰动 发育会影响成年造血和免疫功能。然后，我们将应用此想法来测试 不同产前叶酸对造血机构的影响。增殖，基因组稳定性和细胞 甲基化都是受叶酸介导的OCM影响的所有过程，已知会影响HSC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HSC 功能。孕产妇营养如何影响干细胞结局的根本问题没有被忽视。我们的 初步数据表明，暴露于不同产前叶酸会导致HSC建立的改变。 此外，我们的产前叶酸模型代谢在胎儿生活中持续存在的HSC 成年，功能改变。这些变化部分是由代谢基因表达的差异驱动的。 通过检查产前叶酸如何改变HSC的功能，我们将成为第一个直接识别效果的实验室之一 通过影响HSC的建立和功能，产妇营养对健康后果的营养。此外 其中包含的研究声明，我制定了一个培训计划，我相信可以确保我的成功 在拟议的研究计划的各个方面。我制定的培训计划不仅解决了 培训需求特定于该提案，但也基于我的利益，这将为我提供调查的工具 代谢编程，集成的“ OMIC”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的培训以及职业 开发技能，例如精通精神，写作技巧和演示技巧和学术专业精神。 该提案中包含的所有研究将在犹他大学的Beaudin实验室进行。