Metabolic Regulation of erythropoiesis

红细胞生成的代谢调节

基本信息

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
项目类别：
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

项目摘要

(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.

（请以 WORD 形式保存，请勿以 PDF 形式保存）在此处输入文本，该文本是您的应用程序的新摘要信息。此部分的文本长度不得超过 30 行。贫血是一种常见疾病，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。虽然贫血可能是由红系祖细胞的内在缺陷引起的，但最常见的贫血形式是影响红细胞生成的外在缺陷。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。组织损伤或感染引起的炎症会改变骨髓造血，使骨髓细胞的造血偏向骨髓细胞，但会损害稳态红细胞生成。红细胞输出的这种损失可以通过应激性红细胞生成来补偿。应激性红细胞生成在小鼠和人类之间高度保守。与依赖于持续产生的稳态红细胞生成不同，应激性红细胞生成会产生大量新红细胞，维持体内平衡，直到炎症根源得到解决。与其他基于干细胞的组织再生系统一样，应激红细胞生成会产生瞬时扩增的未成熟应激红系祖细胞（TA-SEP）群体，然后转变为分化为红细胞的定向红系祖细胞群体。 SEPs TA 群体的扩张代表了应激性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。在此关键时期，是什么机制推动了 TA-SEP 的扩散？我们之前的工作表明，TA-SEP 采用以糖酵解和糖酵解代谢物穿梭至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。抑制 NO 产生可阻止 TA-SEP 的增殖并减缓炎症性贫血小鼠模型的恢复。除了 NO 之外，我们的数据表明 Wnt/b-catenin 和 Yap1 信号传导是 TA-SEP 增殖所必需的。在本提案中，我们将在两个目标中解决调节这种增殖代谢的机制。在目标 1 中，我们将探讨 NO 依赖性信号传导在调节 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，我们将探讨 NO、Wnt 和 Yap1 在调节谷氨酰胺代谢中的作用。