Metabolic Regulation of erythropoiesis

（请保持文字，不要PDF） 在此输入文本，它是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，可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在缺陷。缺铁性贫血是一种常见的贫血类型。由组织损伤或感染引起的炎症改变骨髓造血，以稳态红细胞生成为代价使生成偏向于骨髓细胞。这种红细胞输出的损失通过应激红细胞生成来补偿。应激性红细胞生成在小鼠和人之间是高度保守的。与依赖于恒定产生的稳态红细胞生成不同，应激红细胞生成产生一团新的红细胞，其维持体内平衡，直到炎症的来源可以被解决。与其他基于干细胞的组织再生系统一样，应激红细胞生成产生未成熟应激红系祖细胞（TA-SEP）的瞬时扩增群体，其然后转变为分化成红细胞的定向红系祖细胞群体。SEP的TA群体的扩增代表应激红细胞生成的关键阶段。如果产生的TA-SEP太少，随后产生的红细胞将不足以维持体内平衡。该提案将解决这一过程中的一个悬而未决的问题。在这一关键时期，是什么机制驱动了TA-SEP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进入合成代谢途径为特征的增殖代谢。这种代谢的建立需要一氧化氮（NO）依赖性信号传导。在炎性贫血的小鼠模型中，抑制NO的产生阻断了TA-SEP的增殖并减缓了恢复。除了NO，我们的数据显示Wnt/b-连环蛋白和Yap 1信号传导是TA-SEP增殖所必需的。在这个建议中，我们将在两个目标中解决调节这种增殖代谢的机制。在目标1中，我们将讨论NO依赖性信号在调节TA-SEP中关键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Yap 1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.