Metabolic regulation of human erythropoiesis

人类红细胞生成的代谢调节

• 批准号: 10013235
• 负责人: Sandrina KINET
• 金额: $ 13.51万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-30 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013235
• 关键词: Address; Amino Acids; Anemia; Antibodies; Autophagocytosis; Biochemical Pathway; Bioinformatics; Blood; Cell Differentiation process; Cell Survival; Cell division; Cell membrane; Cell physiology; Cells; Cellular Metabolic Process; Chromatin; Citric Acid Cycle; Collection; Data; Defect; Development; Diamond-Blackfan anemia; Dioxygenases; Disease; Down-Regulation; Dysmyelopoietic Syndromes; Enzymes; Epigenetic Process; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Erythropoietin; Fatty Acids; Focus Groups; Genetic Transcription; Genomics; Glucose; Glucose Transporter; Glutamine; Glycolysis; Goals; Hematopoietic Stem Cell Specification; Hematopoietic stem cells; Human; Individual; Inherited; Isotopes; Knowledge; Lamin Type B; Lamins; Ligand Binding Domain; Ligands; Link; Lipids; Lymphoid; Maps; Mediator of activation protein; Metabolic; Metabolic Pathway; Metabolism; Methylation; Mitosis; Modeling; Monitor; Motivation; Mutate; Myelogenous; Nuclear Lamin; Nutrient; Pathologic; Patients; Pentosephosphate Pathway; Permeability; Physiological; Process; Proteins; Reagent; Regulation; Resources; Retroviridae; Role; Surface; Tracer; Up-Regulation; alpha ketoglutarate; base; biomarker discovery; cofactor; cytokine; data integration; embryonic stem cell; epigenome; erythroid differentiation; hematopoietic stem cell niche; individual variation; insight; novel; novel therapeutics; overexpression; progenitor; programs; receptor; receptor binding; self-renewal; single-cell RNA sequencing; small hairpin RNA; solute; stem cells; synergism; transcription factor; transcriptomics

Project 3 Abstract Metabolic regulation of human erythropoiesis The self renewal capacity of hematopoietic stem cells (HSCs) is controlled by the cells' metabolic state but the possibility that nutrient entry and metabolism contribute to the differential commitment of an HSC to a lymphoid, myeloid or erythroid lineage fate was not considered until very recently. The overall goal of this project is to develop a mechanistic understanding of the role of cell metabolism in physiological and disordered erythropoiesis. Our studies address the hypothesis that nutrient transport and utilization regulate both normal and pathological human erythroid differentiation. Our previous data show that the glucose transporter Glut1 is only upregulated during the final mitoses of human erythroid differentiation (Montel- Hagen et al. Cell 2008) whereas the glutamine transporter ASCT2 is expressed on all HSCs. We determined that down regulation of ASCT2 or blocking glutamine metabolism abrogates erythroid differentiation and skews erythropoietin-treated HSCs towards a myeloid fate. In contrast, diverting glucose into the pentose phosphate pathway, away from glycolysis, accelerates erythropoiesis (Oburoglu et al. Cell Stem Cell 2014). In Aim 1, we will use our unique collection of retroviral envelope receptor binding domains (RBDs), that function as specific ligands of solute carrier (SLC) nutrient transporters, to characterize stage- specific expression and function of transporters and determine the array of transporters regulating erythropoiesis in normal conditions as well as in erythroid progenitors with altered nuclear lamins (with Project 4), in a TET2-deficient model of myelodysplastic syndrome, and in RPL5- and RPL11-deficient models of Diamond Blackfan anemia (with Project 1). In Aim 2, we will assess metabolic fluxes from stable glucose, glutamine, and fatty acid isotope tracers, elucidating the metabolic networks and metabolites that regulate normal and perturbed erythropoiesis. These studies will critically address our hypothesis that fuel resource utilization governs early and terminal erythroid differentiation, at a level beyond simply providing the ATP, amino acids and lipids that are required for cell division. We propose that metabolic changes contribute to stage-specific epigenetic, transcriptional and translational erythroid regulatory programs which will be evaluated with Project 2. We anticipate that integration of these data within the Program Project will identify the nutrient fluxes and utilization that control stage-specific erythroid transitions, pioneer nutrient transporter biomarker discovery in erythroid disorders, and promote the manipulation of nutrient transporters and metabolic networks that orient physiological and pathological erythroid cell differentiation and survival.

项目3摘要 人类红细胞生成的代谢调节 造血干细胞（HSC）的自我更新能力由细胞的代谢状态控制，但 营养进入和代谢有助于HSC对A的差异承诺的可能性 直到最近才考虑淋巴样，髓样或红系谱系命运。总体目标 项目是对细胞代谢在生理和生理和 无序的红细胞生成。我们的研究解决了营养运输和利用规范的假设 正常和病理性的人类红细胞分化。我们以前的数据表明葡萄糖 转运蛋白GLUT1仅在人类红细胞分化的最终有丝分裂（montel-- Hagen等。 Cell 2008）而谷氨酰胺转运蛋白ASCT2在所有HSC上表达。我们 确定调节ASCT2或阻塞谷氨酰胺代谢会废除红细胞 分化和偏向红细胞生成素治疗的HSC朝着髓样命运。相反，转移葡萄糖 进入戊糖磷酸盐途径，远离糖酵解，加速了促红细胞生成（Oburoglu等。细胞。 干细胞2014）。在AIM 1中，我们将使用我们独特的逆转录病毒信封受体结合域的集合 （rbds），该功能充当溶质载体（SLC）营养转运蛋白的特定配体，以表征分期 转运蛋白的特定表达和功能，并确定调节转运蛋白的阵列 在正常条件下以及核层粘蛋白改变的红细胞祖细胞中的红细胞生成 项目4），在骨髓增生综合征的TET2缺陷模型中，在RPL5-和RPL11缺陷中 Diamond Blackfan贫血的模型（项目1）。在AIM 2中，我们将评估稳定的代谢通量 葡萄糖，谷氨酰胺和脂肪酸同位素示踪剂，阐明代谢网络和代谢物 调节正常和扰动的红细胞生成。这些研究将严格解决我们的假设，即燃料 资源利用率控制着早期和终末红细胞分化，在一个层面上，不仅仅提供 细胞分裂所需的ATP，氨基酸和脂质。我们建议代谢变化 有助于特定阶段的表观遗传学，转录和翻译红细胞调节计划 将通过项目2进行评估。我们预计这些数据在程序项目中将集成 确定控制阶段特异性红细胞过渡的营养通量和利用率，先锋营养素 红细胞疾病中的转运蛋白生物标志物发现，并促进营养的操纵 转运蛋白和代谢网络，这些网络具有定向生理和病理红细胞分化 和生存。