Metabolic Programming of Hematopoietic Stem Cell Function by Prenatal Folate

摘要 本项目的目的是确定产前叶酸水平对造血干细胞（HSC）的影响 设置和功能。健康和疾病的发展起源（DOHaD）假说声称， 许多成人发病的疾病起源于围产期发育期间。这种发展的现象 疾病的程序化已经被证明至少部分是由表观遗传变化介导的 在发展过程中，因为这些影响也发生跨代。叶酸是一种主要的营养成分 在胎儿期调节细胞甲基化和表观遗传模式，产前叶酸缺乏是 与神经管闭合失败独立相关。全民叶酸强化用于 世界上许多地方都在预防神经管缺陷（NTD），因为大约70%的NTD是 通过补充叶酸来预防。我们将检验不同的产前叶酸水平计划 通过改变造血干细胞功能和随后的免疫轨迹， 发展阶段向前推进。在这项研究中，我们提出，成年人的异质性，功能和输出 在早期发育过程中，HSC区室可以通过扰动形成。我们之前的研究 产前炎症对造血系统发育的影响表明， 发育可影响成人造血和免疫功能。然后，我们将应用这个想法来测试 不同产前叶酸对造血建立的影响。增殖、基因组稳定性和细胞 甲基化都是受叶酸介导的OCM影响的过程，并且已知会影响HSC的建立 和功能我们认为，叶酸介导的OCM的早期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尚未得到充分探讨。我们 初步数据显示，暴露于不同的产前叶酸导致HSC建立的改变。 此外，我们的产前叶酸代谢模型在胎儿期对HSC进行重编程， 成年后功能改变。这些变化部分由代谢基因表达的差异驱动。 通过研究产前叶酸如何改变HSC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HSC的建立和功能，母体营养对健康产生影响。除了 根据其中的研究声明，我制定了一个培训计划，我相信这将确保我的成功 研究计划的各个方面。我制定的培训计划不仅涉及 针对本提案的培训需求，但也基于我的兴趣，这将为我提供调查工具 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的培训，以及职业培训。 发展技能，如指导重点，写作技能和演讲技巧和学术专业精神。 本提案中包含的所有研究将在犹他州大学的博丁实验室进行。

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.