The role of ascorbate in myelopoiesis and infection

抗坏血酸在骨髓生成和感染中的作用

• 批准号: 10582571
• 负责人: Michalis Agathocleous
• 金额: $ 36.08万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582571
• 关键词: Address; Ascorbic Acid; Bacteremia; Biological Assay; Blood Cells; Bone Marrow; COVID-19; Cell Lineage; Cell Separation; Cells; Clonal Expansion; Communicable Diseases; Data; Diet; Elderly; Enzymes; Evolution; Frequencies; Generations; Genetic Engineering; Gulo; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; L-gulonolactone oxidase; Malaria; Measures; Mediating; Methods; Morbidity - disease rate; Multipotent Stem Cells; Mus; Mutation; Myelogenous; Myeloid Cells; Myelopoiesis; Nature; Organism; Outcome; Oxidases; Parasites; Pathogenesis; Pathogenicity; Pathology; Persons; Phenotype; Physiological; Plasma; Plasmodium; Plasmodium chabaudi; Population; Primates; Public Health; Regulation; Rodent; Role; Spleen; Testing; Tissues; Transplantation; Variant; Vertebrates; Work; ascorbate; cell type; cofactor; cytokine; enzyme activity; experimental study; gulonolactone; high risk; human model; in vivo; leukemogenesis; loss of function mutation; malaria infection; metabolic profile; metabolome; metabolomics; mortality; mortality risk; mouse model; mutant; novel; progenitor; response; sodium DEPENDENDENT vitamin C transporter 1; stem; stem cell function; stem cells

PROJECT SUMMARY: We have developed methods to profile the metabolome of hematopoietic stem cells (HSCs) and other rare cell types purified from tissues. Each hematopoietic cell type had a distinct metabolite identity. Most metabolites were enriched or depleted in specific cell types, suggesting they may have novel cell-type specific roles. HSCs and multipotent progenitors (MPPs) in mouse and human bone marrow had high levels of ascorbate (Vitamin C), which promoted the activity of the enzyme TET2, a suppressor of HSC function. Hematopoietic-specific ascorbate deficiency promoted HSC function, myelopoiesis and the generation of inflammatory myeloid cells, and caused early lethality. Ascorbate deficiency is common in the human population because in early primate evolution we lost the ability to synthesize ascorbate. Ascorbate deficiency in healthy people is associated with increased risk of mortality for unknown reasons. Hematopoietic TET2 loss of function mutations are also common in humans, and drive a clonal expansion of mutant blood cells termed clonal hematopoiesis. TET2- deficient blood cells may contribute to an increased risk of mortality. This application’s objective is to understand the role of ascorbate in the regulation of myelopoiesis. Our central hypothesis is that ascorbate suppresses myelopoiesis, and that ascorbate deficiency increases myelopoiesis and inflammation after plasmodium infection. To test this hypothesis, we will use genetically engineered ascorbate deficient mice, to mimic the human condition, and Tet2-deficient mice. In Aim 1 we will test if ascorbate suppresses the generation of inflammatory myeloid cells by acting on HSCs or restricted myeloid progenitors, and if this is mediated by Tet2. In Aim 2 we will determine the effects of ascorbate deficiency or Tet2 deficiency on the myelopoietic response to Plasmodium infection in a mouse model of malaria. In Aim 3 we will investigate the mechanisms by which ascorbate deficiency and Tet2 deficiency promote morbidity and mortality in Plasmodium infection. These experiments may have significant public health implications. They could identify physiological situations, such as infection, in which the presence of ascorbate deficiency and Tet2-deficient clonal hematopoiesis are deleterious to the organism. They may also identify mechanisms by which aberrant myelopoiesis contributes to the pathogenesis of malaria which afflicts more than 200 million people worldwide.

项目概要： 我们已经开发出方法来分析造血干细胞（HSC）和其他稀有细胞的代谢组， 从组织中提纯的类型。每种造血细胞类型具有不同的代谢物特性。大多数代谢产物 在特定的细胞类型中富集或耗尽，这表明它们可能具有新的细胞类型特异性作用。HSCs 小鼠和人骨髓中的多能祖细胞（MPPs）具有高水平的抗坏血酸（维生素C） C），其促进酶TET 2的活性，所述酶TET 2是HSC功能的抑制剂。造血特异性 抗坏血酸缺乏促进HSC功能、骨髓生成和炎性骨髓细胞的产生， 并导致早期致命。抗坏血酸缺乏症在人类中很常见，因为在早期灵长类动物中， 在进化过程中，我们失去了合成抗坏血酸的能力。健康人的抗坏血酸缺乏与 不明原因的死亡风险增加。造血TET 2功能丧失突变也是 在人类中很常见，并驱动突变血细胞的克隆扩增，称为克隆造血。TET2- 缺乏血细胞可能导致死亡风险增加。此应用程序的目标是 了解抗坏血酸在骨髓生成调节中的作用。我们的核心假设是抗坏血酸 抑制骨髓生成，抗坏血酸缺乏会增加骨髓生成和炎症， 疟原虫感染为了验证这一假设，我们将使用基因工程抗坏血酸缺乏小鼠， 模拟人类和Tet 2缺陷小鼠的情况。在目标1中，我们将测试抗坏血酸盐是否抑制 通过作用于HSC或限制性骨髓祖细胞产生炎性骨髓细胞，如果这是 由Tet 2介导。在目标2中，我们将确定抗坏血酸缺乏或Tet 2缺乏对 疟疾小鼠模型中对疟原虫感染的骨髓生成反应。在目标3中，我们将调查 抗坏血酸缺乏和Tet 2缺乏促进糖尿病发病率和死亡率的机制 疟原虫感染。这些实验可能会对公共卫生产生重大影响。他们可以识别 生理情况，如感染，其中存在抗坏血酸缺乏和Tet 2缺乏 克隆造血对生物体有害。他们还可以识别异常的 骨髓生成是疟疾发病机制的一部分，疟疾在全世界折磨着2亿多人。