Metabolic regulation of hematopoietic stem cell specification and function

造血干细胞规格和功能的代谢调节

• 批准号: 8630939
• 负责人: TRISTA E. NORTH
• 金额: $ 37.85万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630939
• 关键词: Acute; Adult; Aorta; Birth; Birth Weight; Blood; Blood Cells; Blood Glucose; Catabolism; Cell Lineage; Cell physiology; Cessation of life; Chronic; Clinical Trials; Data; Defect; Diabetes Mellitus; Disease; Dorsal; Dose; Embryo; Embryonic Development; Endothelium; FDA approved; Fluorescence Microscopy; Foundations; Gene Expression; Gene Expression Regulation; Generations; Genes; Gestational Diabetes; Glucose; Goals; Gonadal structure; Growth; Health; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Human; Hyperglycemia; Hypoxia; Immune system; Immunity; In Vitro; Incidence; Individual; Injury; Investigation; Lead; Location; Longevity; Marrow; Mediating; Mesonephric structure; Metabolic; Metabolic Diseases; Metabolism; Modeling; Mus; Nutrient; Obesity; Organism; Outcome; Output; Oxygen; Pancytopenia; Physiological; Placenta; Production; RUNX1 gene; Radiation Injuries; Reactive Oxygen Species; Recovery; Regulation; Research; Risk; Site; Staging; Stem Cell Development; Stem cell transplant; Stem cells; Therapeutic; Time; Transcriptional Regulation; Umbilical Cord Blood; Vertebrates; Work; Zebrafish; cellular targeting; chemical genetics; functional genomics; glucose metabolism; glucose uptake; in vivo; insight; leukemia; molecular dynamics; novel; repaired; response; self-renewal; stem cell fate specification; transcription factor

DESCRIPTION (provided by applicant): Metabolic disorders, including obesity and diabetes, are the leading cause of preventable death in the U.S. The incidence of gestational diabetes has similarly increased. The impact of physiologically elevated glucose levels on hematopoiesis is not established. Hematopoietic stem cells (HSCs) are essential for survival, as they function to produce each of the mature blood cell lineages throughout the lifespan of the organism. The first HSCs arise from hemogenic endothelium in the aorta-gonad-mesonephros (AGM) region. Most genes involved in HSC formation, such as RUNX1, are highly conserved across vertebrates, and continue to regulate HSC homeostasis in the adult. We have successfully used zebrafish to identify novel regulators of vertebrate HSCs, resulting in the first FDA-approved clinical trial originating from zebrafish studies. To assess the impact of metabolic regulation on HSCs, we exposed zebrafish embryos to increasing physiological doses of glucose and observed that elevated glucose levels enhanced the timing and magnitude of embryonic HSC formation. Our long-term goal is to characterize the impact of nutrient availability on HSC formation and function. Our objective here is to characterize the effects of modulation of glucose metabolism on HSC induction, proliferation and differentiation in the vertebrate embryo. Our central hypothesis is that glucose- metabolism impacts HSC formation via production of ROS and subsequent hif1α stabilization to drive coordinate expression of hematopoietic genes. The rationale for our work is that an understanding of the impact of physiological glucose fluctuations on HSCs will elucidate potential risks of dysregulated metabolism on the hematopoietic system, which has long-term consequences for immunity. In Specific Aim 1, we will assess the impact of excess glucose on the spatio-temporal onset and progression of HSC development. Using chemical and genetic modulation of metabolism, we will identify the mechanism by which glucose impacts HSC-related transcriptional regulation via hif1α. Our preliminary data show physiological glucose elevation significantly accelerates HSC induction. In Specific Aim 2, we will assess the impact of acute versus chronic hyperglycemia and coordinated hif1α target gene regulation on HSC function. We will confirm the evolutionary conservation of these effects in an adult injury model, murine gestational diabetes models and in human umbilical cord blood. Our preliminary data indicate glucose exposure enhances recovery after marrow injury and hif1α activity in the AGM and placenta correlates with HSC production, suggesting glucose metabolism is a conserved regulatory factor. The expected outcomes of this proposal are a detailed understanding of the spatio-temporal dynamics and molecular mechanisms of glucose metabolism-mediated HSC regulation. These results will provide insight into how the developing organism senses and responds to fluctuations in nutrient supply to match hematopoietic output with anticipated growth rates, and will have a direct impact on our understanding of the risks of gestational diabetes on hematopoiesis and for therapeutic HSC modulation.

描述（由申请人提供）：代谢性疾病，包括肥胖和糖尿病，是美国可预防死亡的主要原因，妊娠期糖尿病的发病率也有类似的增加。生理性血糖水平升高对造血的影响尚未确定。造血干细胞（hsc）是生存所必需的，因为它们的功能是在生物体的整个生命周期中产生每种成熟的血细胞谱系。第一批造血干细胞起源于主动脉-性腺-中肾区（AGM）的造血内皮。大多数参与HSC形成的基因，如RUNX1，在脊椎动物中是高度保守的，并且在成人中继续调节HSC的稳态。我们已经成功地利用斑马鱼来鉴定脊椎动物造血干细胞的新调节剂，从而进行了第一个fda批准的源自斑马鱼研究的临床试验。为了评估代谢调节对HSC的影响，我们将斑马鱼胚胎暴露于增加生理剂量的葡萄糖中，观察到葡萄糖水平升高会增加胚胎HSC形成的时间和强度。我们的长期目标是表征营养供应对HSC形成和功能的影响。我们的目的是表征糖代谢调节对脊椎动物胚胎HSC诱导、增殖和分化的影响。我们的中心假设是，葡萄糖代谢通过ROS的产生和随后的hif1α稳定来驱动造血基因的协调表达，从而影响HSC的形成。我们工作的基本原理是理解生理葡萄糖波动的影响