Metabolic Regulation of erythropoiesis

红细胞生成的代谢调节

• 批准号: 10655878
• 负责人: ROBERT Frank PAULSON
• 金额: $ 31.6万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655878
• 关键词: Adopted; Affect; Amino Acid Transporter; Amino Acids; Anabolism; Anemia; Anemia due to Chronic Disorder; Bolus Infusion; Bone Marrow; Carbon; Cell Proliferation; Compensation; Coupled; Data; Defect; Enzymes; Erythrocytes; Erythroid; Erythroid Progenitor Cells; Erythropoiesis; Erythropoietin; Fructose; GDF15 gene; Generations; Glutamine; Glycine; Glycolysis; Health; Hematopoiesis; Hemolytic Anemia; Homeostasis; Human; Infection; Inflammation; Inflammatory; Iron deficiency anemia; Lipids; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Mus; Mutation; Myeloid Cells; Myelopoiesis; Nitric Oxide; Nucleotides; Output; Pathway interactions; Pentosephosphate Pathway; Phosphotransferases; Population; Process; Production; Proliferating; Purines; Pyruvate Kinase; Quality of life; Recovery; Red Blood Cell Count; Regulation; Role; Serine; Signal Pathway; Signal Transduction; Source; Stress; Supporting Cell; System; Text; Thalassemia; Tissues; Translations; WNT Signaling Pathway; Work; amino acid metabolism; aminoacid biosynthesis; beta catenin; biological adaptation to stress; blood glucose regulation; critical period; design; dimer; erythroid differentiation; macromolecule; mortality; mouse model; novel therapeutics; progenitor; purine metabolism; stem cells; tissue regeneration; transcription factor; uptake

(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.

（请保持言语，不要PDF） 在此处输入文本，这是您应用程序的新摘要信息。本节必须不超过30行文本。 贫血是一种常见的疾病，会引起明显的发病率和死亡率，并对生活质量产生负面影响。尽管贫血可能是由红细胞祖细胞中固有缺陷引起的，但最常见的贫血形式是影响红细胞生成的外部缺陷。铁缺乏贫血后，炎症的贫血是第二大常见的贫血形式。由组织损伤或感染引起的炎症改变了骨髓造血，偏向髓样细胞，以稳定的红细胞生成为代价。红细胞输出的这种损失是通过压力红细胞生成的。压力红细胞生成在小鼠和人之间高度保守。与依赖持续产生的稳态红细胞生成不同，压力红细胞生成会产生大量的新红细胞，可维持稳态，直到可以解决炎症的来源。与其他基于干细胞的组织再生系统一样，压力红细胞生成会产生瞬态的不成熟胁迫粒子祖细胞（TA-SEPS）的瞬态扩增群体，然后将其转换为差异为erythrocytes的批准的厄森阿罗伊祖细胞的群体。 SEP的TA种群的扩展代表了压力红细胞生成的关键阶段。如果产生太少的ta-seps，则随后的红细胞生产将不足以维持体内平衡。该建议将解决此过程中的一个杰出问题。在这个关键时期，什么机制驱动了ta-seps的扩散。我们以前的工作表明，TA-SEP采用了一种增生性代谢，其特征是糖酵解和将糖酵解代谢物穿梭到合成代谢途径中。这种新陈代谢的建立需要一氧化氮，否，依赖性信号。在炎症性贫血的鼠模型中，抑制无生产可以阻止TA-SEPS的增殖和减慢恢复。除NO之外，我们的数据还表明，wnt/b-catenin和Yap1信号是增殖Ta-Seps所需的。在该提案中，我们将在两个目标中解决调节这种增殖代谢的机制。在AIM 1中，我们将解决NO依赖信号传导在调节关键糖酵解酶，丙酮酸激酶M2和磷酸果糖-2-激酶/果糖2,6-双磷酸酶4中的作用中的作用。在AIM 2中，我们将解决NO，WNT和YAP1在调节谷氨酰胺代谢中的作用。