Metabolic Control of Erythroid Differentiation

红细胞分化的代谢控制

基本信息

批准号：
9885429
负责人：
ROBERT Frank PAULSON
金额：
$ 30.5万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9885429
关键词：
Address Adopted Adult Alloimmunization Amino Acids Anemia Anemia due to Chronic Disorder BMP4 Blood Transfusion Bolus Infusion Bone Marrow CD34 gene Cell Proliferation Cell division Chromatin Chronic Citric Acid Cycle Data Defect Deposition Development Disease Ensure Erinaceidae Erythrocytes Erythroid Erythroid Progenitor Cells Erythropoiesis Erythropoietin Etiology Extramedullary Fetal Liver Foundations G9a histone methyltransferase GDF15 gene Gene Expression Generations Glucose Glutamine Glycine Glycolysis Health Hematopoietic stem cells Hemoglobin Homeostasis Human Hypoxia Impairment Infection Inflammation Inflammatory Lipids Liver Megakaryocytes Metabolic Metabolic Control Metabolism Mitochondria Modeling Mus NIH Program Announcements Nucleotides Pathology Pathway interactions Pentosephosphate Pathway Phase Physiological Population Process Procollagen-Proline Dioxygenase Production Proliferating Property Proteins Quality of life Recovery Red Blood Cell Count Regulation Repression Respiration Risk Role Serine Serum Sickle Cell Anemia Signal Transduction Spleen Stable Isotope Labeling Stress Succinates System Thalassemia Time Transfusion Work aerobic glycolysis blood treatment chemotherapy chromatin modification design effective therapy erythroid differentiation histone methyltransferase hypoxia inducible factor 1 immunoregulation novel strategies novel therapeutics premature progenitor programs recombinant human erythropoietin reconstitution response standard care stem cells tissue oxygenation

项目摘要

Project summary: Anemia is a significant human health problem that is caused by multiple etiologies and has negative impact on quality of life. Standard treatments for anemia are transfusion therapy and treatment with erythropoiesis stimulating agents, which can be effective in the short-term, but are not without risk. Treatment of chronic anemia with transfusion therapy is complicated by the risk of allo-immunization and the potential for infection. While, erythropoiesis stimulating agents are not effective treatments for all anemia and their immunomodulatory properties can compromise other treatments. These observations point to a need in the field to identify new treatments for anemia. One possibility is to characterize the physiological response to anemic stress. Previous work in my lab showed that in response to hypoxic stress, bone marrow steady state erythropoiesis is unable to maintain homeostasis. At these times, stress erythropoiesis predominates. Stress erythropoiesis is best understood in the murine system where it is extra-medullary, occurring in the adult spleen and liver and in the fetal liver during development. Stress erythropoiesis utilizes a different strategy than steady state erythropoiesis. Instead of generating new erythrocytes at a constant rate, stress erythropoiesis generates a bolus of new erythrocytes designed to alleviate anemia until steady state erythropoiesis can resume. This strategy relies on the ability of immature stress erythroid progenitors to proliferate without differentiating. The expansion of this transient amplifying population is an essential step in stress erythropoiesis. If too few early progenitors are generated or if they differentiate prematurely, insufficient erythrocytes will be produced to alleviate the anemia. In this proposal submitted under the SHINE II program announcement, we will focus on the mechanisms that regulate the expansion of early stress progenitors and the mechanisms that inhibit their differentiation during this expansion phase. We hypothesize that stress erythroid progenitors adopt a pro-inflammatory metabolism characterized by increased glucose and glutamine metabolism, which results in the production of anabolic intermediates needed to produce lipids, nucleotides and amino acids necessary for cell proliferation. In addition, this metabolic program produces metabolites that promote the activity of histone methylases that maintain repression of the erythroid differentiation program. This model demonstrates how metabolic regulation can coordinate the proliferation and differentiation of stress erythroid progenitors during the recovery from anemic stress.

项目概要：贫血是由多种病因引起的严重的人类健康问题，对生活质量产生负面影响。贫血的标准治疗方法是输血疗法和药物治疗红细胞生成刺激剂，短期内有效，但并非没有风险。治疗慢性贫血的输血治疗由于同种免疫的风险和潜在的潜在风险而变得复杂化。感染。然而，红细胞生成刺激剂并不能有效治疗所有贫血及其相关疾病。免疫调节特性可能会影响其他治疗。这些观察表明需要领域以确定贫血的新疗法。一种可能性是描述生理反应贫血压力。我实验室之前的工作表明，为了应对缺氧应激，骨髓稳态红细胞生成无法维持体内平衡。在这些时候，应激性红细胞生成占主导地位。压力红细胞生成在小鼠系统中最容易被理解，它发生在成人的髓外脾脏和肝脏以及发育过程中的胎儿肝脏。应激性红细胞生成采用的策略与稳态红细胞生成。应激红细胞生成不是以恒定速率生成新红细胞产生大量新红细胞，旨在缓解贫血，直到红细胞生成达到稳定状态恢复。该策略依赖于未成熟的应激红系祖细胞在无压力的情况下增殖的能力。差异化。这种瞬时扩增群体的扩张是应对压力的重要一步红细胞生成。如果产生的早期祖细胞太少或者它们过早分化，则不足以将产生红细胞以缓解贫血。在根据 SHINE II 计划提交的这份提案中声明中，我们将重点关注调节早期应激祖细胞扩张的机制和在此扩展阶段抑制其分化的机制。我们假设压力红系祖细胞采用促炎代谢，其特征是葡萄糖和谷氨酰胺增加新陈代谢，导致产生脂质、核苷酸所需的合成代谢中间体以及细胞增殖所必需的氨基酸。此外，该代谢程序产生的代谢物促进组蛋白甲基化酶的活性，维持红细胞分化程序的抑制。该模型展示了代谢调节如何协调应激的增殖和分化从贫血应激恢复期间的红系祖细胞。