Metabolic Control of Erythroid Differentiation

项目摘要：贫血是一种重要的人类健康问题，由多种原因引起， 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 促红细胞生成剂，短期内有效，但也不是没有风险。治疗 输血治疗的慢性贫血的风险因异体免疫的风险和潜在的 感染。然而，促红细胞生成药物并不是治疗所有贫血和他们的有效方法 免疫调节特性可能会影响其他治疗方法。这些观察表明，有必要在 以确定治疗贫血症的新方法。一种可能性是将生理反应描述为 贫血压力。我实验室以前的工作表明，在应对低氧应激时，骨髓处于稳定状态 红细胞生成不能维持动态平衡。在这些时候，应激性红细胞生成占主导地位。压力 在小鼠的系统中，红细胞生成是最好的理解，因为它发生在成人的髓外。 在发育过程中，脾和肝脏以及胎儿肝脏中。应激性红细胞生成使用一种不同于 稳定状态下的红细胞生成。不是以恒定的速度产生新的红细胞，而是强调红细胞生成 生成一批新的红细胞，旨在缓解贫血，直到稳定状态的红细胞生成 继续播放。这一策略依赖于未成熟的应激红系祖细胞在没有 差异化。这种暂时性放大人口的扩大是压力的重要一步。 红血球生成。如果产生的早期祖细胞太少，或者如果它们过早分化，就不足以 红血球将被制造出来以缓解贫血。在根据SHARE II计划提交的这份提案中 宣布，我们将集中在调节早期应激前体细胞和 在这一扩张阶段抑制其分化的机制。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 新陈代谢，它导致合成代谢中间产物的产生，这是产生脂质、核苷酸所需的 以及细胞增殖所必需的氨基酸。此外，这一代谢程序产生的代谢物 促进维持抑制红系分化程序的组蛋白甲基酶的活性。 这个模型展示了新陈代谢调节如何协调压力的增殖和分化。 贫血应激恢复过程中的红系祖细胞。

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.