Metabolic Regulation of erythropoiesis

(请保存在Word中，不要保存为PDF) 在此输入文本，它是您的应用程序的新摘要信息。此部分不得超过30行文本。 贫血是一种常见的疾病，会导致严重的发病率和死亡率，并对生活质量产生负面影响。虽然贫血可以由红系祖细胞的内在缺陷引起，但最常见的贫血形式是影响红细胞生成的外源性缺陷。继缺铁性贫血之后，炎症性贫血是第二种最常见的贫血形式。由组织损伤或感染引起的炎症改变了骨髓的造血，以稳定的红细胞生成为代价，使生产向髓系细胞倾斜。这种红系输出的损失被应激性红血球生成所补偿。应激性红细胞生成在小鼠和人之间高度保守。与稳定状态的红细胞生成不同，稳定状态的红细胞生成依赖于持续的生产，而应激生成的红细胞会产生一大批新的红细胞，维持体内平衡，直到炎症的根源得到解决。与其他基于干细胞的组织再生系统一样，应激红系祖细胞产生一瞬间扩增的未成熟应激红系祖细胞(TA-SEP)群体，然后转化为定向分化为红细胞的红系祖细胞群体。SEP的TA群体的扩大代表了应激性红细胞生成的一个关键阶段。如果TA-SEP产生太少，随后产生的红细胞将不足以维持体内平衡。这项提议将解决这一进程中的一个悬而未决的问题。在这一关键时期，是什么机制推动了TA-SEPs的增殖。我们以前的工作表明，TA-SEPs采用以糖酵解和糖酵解代谢产物穿梭到合成代谢途径为特征的增殖代谢。这种新陈代谢的建立需要依赖于一氧化氮、一氧化氮的信号传导。抑制NO的产生阻止了TA-SEP的增殖，并减缓了炎症性贫血小鼠模型的恢复。除了NO外，我们的数据还表明，Wnt/b-catenin和YAP1信号是TA-SEPs增殖所必需的。在这项提案中，我们将从两个方面探讨调节这种增殖新陈代谢的机制。在目标1中，我们将讨论NO依赖信号在调节TA-SEPs中关键的糖酵解酶丙酮酸激酶M2和磷酸果糖-2-激酶/果糖2，6-二磷酸酶4活性中的作用。在目标2中，我们将讨论NO、Wnt和YAP1在调节谷氨酰胺代谢中的作用。

(PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Anemia is a common condition that causes significant morbidity and mortality and has a negative impact on quality of life. Although anemia can be caused by intrinsic defects in erythroid progenitor cells, the most common forms of anemia are extrinsic defects that affect erythropoiesis. After iron deficiency anemia, the anemia of inflammation is the second most common form of anemia. Inflammation caused by tissue damage or infection alters bone marrow hematopoiesis, skewing production towards myeloid cells at the expense of steady state erythropoiesis. This loss of erythroid output is compensated by stress erythropoiesis. Stress erythropoiesis is highly conserved between mouse and human. Unlike steady state erythropoiesis, which relies on constant production, stress erythropoiesis generates a bolus of new erythrocytes that maintain homeostasis until the source of the inflammation can be resolved. Like other stem cell-based tissue regeneration systems, stress erythropoiesis generates a transient amplifying population of immature stress erythroid progenitors (TA-SEPs), which then transition to a population of committed erythroid progenitors that differentiate into erythrocytes. The expansion of the TA population of SEPs represents a key stage in stress erythropoiesis. If too few TA-SEPs are generated, the subsequent production of erythrocytes will not be sufficient to maintain homeostasis. This proposal will address an outstanding question in this process. What mechanisms drove the proliferation of TA-SEPs during this critical period. Our previous work showed that TA-SEPs adopt a proliferative metabolism characterized by glycolysis and the shuttling of glycolytic metabolites into the anabolic pathways. The establishment of this metabolism requires nitric oxide, NO, dependent signaling. Inhibition of NO production blocks proliferation of TA-SEPs and slows recovery in a murine model of inflammatory anemia. In addition to NO, our data show that Wnt/b-catenin and Yap1 signaling are required for the proliferation TA-SEPs. In this proposal, we will address in two aims the mechanisms that regulate this proliferative metabolism. In Aim 1, we will address the role of NO dependent signaling in regulating the activity of key glycolytic enzymes, pyruvate kinase M2 and phosphofructo-2-kinase/Fructose 2,6-bisphosphatase 4 in TA-SEPs. In Aim 2, we will address the role of NO, Wnt and Yap1 in regulating glutamine metabolism.