Acetate as a Mediator of Hematopoietic Stem Cell Inflammatory Response and Clonal Hematopoiesis

乙酸作为造血干细胞炎症反应和克隆造血的介质

• 批准号: 10464508
• 负责人: JONATHAN TIESSEN
• 金额: $ 4.68万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464508
• 关键词: ATP Citrate (pro-S)-Lyase; Acetate-CoA Ligase; Acetates; Acetyl Coenzyme A; Adult; Bacterial Infections; Biological Assay; Bolus Infusion; Cells; Cellular biology; ChIP-seq; Chronic; Citrates; Consumption; Cues; Data; Diet; Dietary Component; Disease; Fructose; Gene Expression; Gene Expression Profiling; Genes; Genetic; Goals; Health; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Histone Acetylation; Human; Immune; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferons; Interleukins; Link; Lipopolysaccharides; Literature; Maintenance; Measures; Mediator of activation protein; Metabolic; Metabolism; Modeling; Mus; Mutant Strains Mice; Mutation; Natural regeneration; Phenotype; Production; Proteomics; Public Health; Publishing; Role; Serum; Signal Transduction; Source; Stimulus; Supplementation; Testing; Transplantation; Work; base; cell behavior; cytokine; dietary; epigenetic profiling; epigenetic regulation; immune function; mouse model; mutant; novel; response; single molecule; stem cell function; stem cells; systemic inflammatory response; transcriptome sequencing

PROJECT SUMMARY Hematopoietic stem and progenitor cells (HSPCs) are responsible for the maintenance and regeneration of the adult hematopoietic system. These cells are responsive to systemic cues that influence their differentiation, such as inflammation, in the form of cytokines such as interferons and interleukins. Inflammation is particularly noteworthy for its influence not only in normal hematopoiesis, but as a driver of clonal hematopoiesis (CH), the overrepresentation of specific mutant clones in the hematopoietic system. Mutations in Tet2 represent a common driver of CH, and Tet2 mutant HSPCs expand preferentially in response to inflammatory stimuli. Recently, acetate has been implicated as an inflammation-associated metabolic signal. Acetate rises systemically during inflammation but is also elevated as a byproduct of dietary components, particularly fructose. I have found in preliminary studies that supplementing acetate, either directly or through fructose, along with inflammatory stimuli broadly exacerbates inflammation in the form of inflammatory serum cytokines and HSPC inflammatory gene expression. Together, these results suggest a role for acetate as a diet-associated metabolic mediator of inflammation, relevant to both normal and clonal hematopoiesis. Therefore, the focus of this proposal is to 1) interrogate the hematopoietic response to changes in systemic acetate levels during inflammation and to 2) interrogate acetate as a driver of clonal hematopoiesis during inflammation. These aims will be accomplished through a combination of functional, gene expression, and phenotypic studies of HSPCs in response to acetate during inflammation.

项目摘要 造血干和祖细胞（HSPC）负责维持和再生 成人造血系统。这些细胞对影响其分化的全身线索有反应，这样 作为炎症，以干扰素和白细胞素等细胞因子的形式。特别是炎症 值得注意的是，它不仅在正常造血中的影响，而且是克隆造血的驱动器（CH） 造血系统中特定突变克隆的过分占代表性。 TET2中的突变代表常见 CH的驱动器和TET2突变体HSPC响应炎症刺激而优先扩展。最近， 乙酸盐已被认为是与炎症相关的代谢信号。醋酸盐在 炎症，但也被升高为饮食成分的副产品，尤其是果糖。我发现 初步研究，直接或通过果糖补充乙酸盐，以及炎症刺激 广泛加剧炎症血清细胞因子和HSPC炎症基因的形式的炎症 表达。总之，这些结果表明，乙酸盐作为饮食相关的代谢介质的作用 炎症，与正常和克隆造血相关。因此，该提议的重点是1） 询问造血反应对炎症期间全身乙酸水平变化的造血反应和2） 在炎症过程中审问醋酸盐作为克隆造血的驱动器。这些目标将实现 通过响应乙酸的HSPC的功能，基因表达和表型研究的结合 在炎症期间。