Metabolic Control of Erythroid Differentiation
红细胞分化的代谢控制
基本信息
- 批准号:10091511
- 负责人:
- 金额:$ 30.46万
- 依托单位:
- 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:
- 关键词:AddressAdoptedAdultAlloimmunizationAmino AcidsAnemiaAnemia due to Chronic DisorderBMP4Blood TransfusionBolus InfusionBone MarrowCD34 geneCell ProliferationCell divisionChromatinChronicCitric Acid CycleDataDefectDepositionDevelopmentDiseaseEnsureErinaceidaeErythrocytesErythroidErythroid Progenitor CellsErythropoiesisErythropoietinEtiologyExtramedullaryFetal LiverFoundationsG9a histone methyltransferaseGDF15 geneGene ExpressionGenerationsGlucoseGlutamineGlycineGlycolysisHealthHematopoietic stem cellsHemoglobinHomeostasisHumanHypoxiaImpairmentInfectionInflammationInflammatoryLipidsLiverMegakaryocytesMetabolicMetabolic ControlMetabolismMitochondriaModelingMusNIH Program AnnouncementsNucleotidesPathologyPathway interactionsPentosephosphate PathwayPhasePhysiologicalPopulationProcessProcollagen-Proline DioxygenaseProductionProliferatingPropertyProteinsQuality of lifeRecoveryRed Blood Cell CountRegulationRepressionRespirationRiskRoleSerineSerumSickle Cell AnemiaSignal TransductionSpleenStable Isotope LabelingStressSuccinatesSystemThalassemiaTimeTransfusionWorkaerobic glycolysisblood treatmentchemotherapychromatin modificationdesigneffective therapyerythroid differentiationhistone methyltransferasehypoxia inducible factor 1immunoregulationnovel strategiesnovel therapeuticsprematureprogenitorprogramsrecombinant human erythropoietinreconstitutionresponsestandard carestem cellstissue 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.
项目概述:贫血是一个重要的人类健康问题,由多种病因引起,
对生活质量的负面影响。贫血的标准治疗是输血治疗和用
红细胞生成刺激剂,其可以在短期内有效,但并非没有风险。治疗
输血治疗的慢性贫血的并发症是由同种免疫的风险和潜在的
感染然而,红细胞生成刺激剂并不是所有贫血的有效治疗,
免疫调节特性可能损害其它治疗。这些观察表明,
领域,以确定新的治疗贫血。一种可能性是表征对以下物质的生理反应:
贫血压力我实验室以前的工作表明,在对低氧应激的反应中,骨髓稳态
红细胞生成不能维持体内平衡。在这些时候,应激红细胞生成占主导地位。应力
红细胞生成在鼠系统中最好理解,其中它是髓外的,发生在成年人中,
脾脏和肝脏以及发育过程中的胎儿肝脏。应激性红细胞生成利用与应激性红细胞生成不同的策略。
稳态红细胞生成而不是以恒定的速度产生新的红细胞,
产生一团新的红细胞,旨在缓解贫血,直到稳定状态的红细胞生成,
简历这种策略依赖于未成熟应激红系祖细胞在没有应激的情况下增殖的能力。
差异化这种短暂扩增群体的扩张是压力中必不可少的一步
红细胞生成如果产生的早期祖细胞太少,或者如果它们过早分化,
将产生红细胞以减轻贫血。在根据SHINE II计划提交的这份提案中,
公告,我们将重点关注调节早期应激祖细胞扩张的机制,
在这个扩张阶段抑制它们分化的机制。我们假设压力
红系祖细胞采用以葡萄糖和谷氨酰胺增加为特征的促炎代谢
代谢,这导致产生所需的合成代谢中间体,以产生脂质,核苷酸
和细胞增殖所必需的氨基酸。此外,该代谢程序产生代谢物,
促进维持红细胞分化程序抑制的组蛋白甲基化酶的活性。
这个模型演示了代谢调节如何协调应激的增殖和分化
红系祖细胞在从贫血应激中恢复期间。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ROBERT Frank PAULSON其他文献
ROBERT Frank PAULSON的其他文献
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{{ truncateString('ROBERT Frank PAULSON', 18)}}的其他基金
Selenium, Selenoproteins, and Stress Erythropoiesis
硒、硒蛋白和应激性红细胞生成
- 批准号:
10017964 - 财政年份:2019
- 资助金额:
$ 30.46万 - 项目类别:
Selenium, Selenoproteins, and Stress Erythropoiesis
硒、硒蛋白和应激性红细胞生成
- 批准号:
10096670 - 财政年份:2019
- 资助金额:
$ 30.46万 - 项目类别:
Selenium, Selenoproteins, and Stress Erythropoiesis
硒、硒蛋白和应激性红细胞生成
- 批准号:
10197916 - 财政年份:2019
- 资助金额:
$ 30.46万 - 项目类别:
Effect of Omega-3 Fatty Acids on Cancer Stem Cells
Omega-3 脂肪酸对癌症干细胞的影响
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8511593 - 财政年份:2012
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BMP4 Dependent Stress Erythropoiesis Pathway in Short-term Radioprotection
短期辐射防护中 BMP4 依赖性应激红细胞生成途径
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8850435 - 财政年份:2009
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7730716 - 财政年份:2009
- 资助金额:
$ 30.46万 - 项目类别:
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