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.

项目摘要：贫血是由多种病因引起的重大人类健康问题对生活质量的负面影响。贫血的标准治疗方法是输血疗法和治疗促红细胞生成的刺激剂，在短期内可以有效，但并非没有风险。治疗通过输血疗法的慢性贫血的风险使同种免疫的风险和潜力变得复杂感染。而促红细胞动物刺激剂并不是所有贫血及其的有效治疗方法免疫调节特性会损害其他治疗方法。这些观察表明识别贫血的新疗法的领域。一种可能性是表征对贫血的压力。我实验室的先前工作表明，响应低氧应激，骨髓稳态红细胞生成无法维持体内平衡。在这些时候，压力红细胞生成主要为主。压力在成年人中发生的鼠系统中最好理解促红细胞生成发育过程中脾脏和肝脏以及胎儿肝脏中。压力红细胞生成使用与稳态红细胞生成。压力红细胞生成的不是以恒定的速度产生新的红细胞产生大量的新红细胞，旨在减轻贫血，直到稳态红细胞生成可以恢复。该策略依赖于未成熟的压力红细胞祖细胞增殖的能力区分。这种瞬态放大种群的扩展是压力的重要一步红细胞生成。如果产生的早期祖细胞太少，或者它们过早地区分了将产生红细胞来减轻贫血。在Shine II计划下提交的建议中宣布，我们将重点介绍规范早期压力祖细胞扩张的机制和在此扩展阶段抑制其分化的机制。我们假设压力红细胞祖细胞采用促炎的代谢，其特征是葡萄糖和谷氨酰胺增加代谢，导致产生脂质，核苷酸所需的合成代谢中间体的产生和细胞增殖所需的氨基酸。此外，该代谢程序还会产生代谢物促进维持红细胞分化程序抑制的组蛋白甲基酶的活性。该模型展示了代谢调节如何协调应力的增殖和分化从贫血应力恢复期间，红细胞祖细胞。