Metabolic Control of Erythroid Differentiation

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。

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.