Mitochondria in the Regulation of Terminal Erythropoiesis

线粒体对终末红细胞生成的调节

• 批准号: 10587056
• 负责人: SAGHI GHAFFARI
• 金额: $ 53.34万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587056
• 关键词: Address; Area; Biology; Cell Differentiation process; Cell Maturation; Cells; Chromatin; Collaborations; Communication; Computational Biology; Disease; Erythroblasts; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Exhibits; Exposure to; FOXO3A gene; Generations; Genes; Genomic approach; Genomics; Glycolysis; Goals; Hemoglobin; In Situ; Knowledge; Label; Mediating; Membrane Potentials; Metabolic Pathway; Mitochondria; Modeling; Moderate Activity; Morphology; Mus; Nuclear; Organelles; PINK1 gene; Pathway interactions; Phenotype; Phosphotransferases; Physical condensation; Physiological; Positioning Attribute; Process; Production; Property; Pyruvate; Pyruvates; Regulation; Research; Shapes; Technology; Testing; Therapeutic; Therapeutic Intervention; confocal imaging; design; differential expression; efficacious treatment; improved; metabolic profile; metabolomics; mitochondrial membrane; novel therapeutics; programs; segregation; superresolution imaging; transcription factor

PROJECT SUMMARY/ABSTRACT The massive daily production of 200 billion red blood cells (RBCs) requires a remarkable coordination of erythroid cell differentiation and maturation, with processes that are implicated in erythroid enucleation. Alterations in regulatory mechanisms that control the terminal erythroid cell maturation and enucleation are implicated in erythroid and other disorders. Limited knowledge of these processes have been an impediment to therapy interventions and large-scale RBC production. Our long-standing focus on the transcription factor Foxo3 that is a central regulator of terminal erythropoiesis led us to identifying mitochondria as critical and dynamic regulators in these processes. We recently showed that mitochondria are actively regulating erythroid cell enucleation. Notably, we found exogenous pyruvate – a product of glycolysis – but not in situ produced pyruvate via glycolysis fuel mitochondria and sustains erythroid enucleation suggesting an unanticipated and significant function for exogenous pyruvate in this process. Our ongoing studies extend these findings and suggest that ATP-independent mitochondrial functions as well as mitochondrial-related pathways including clearance may be central to terminal erythropoiesis and their alterations implicated in disease. Our combined studies raise the possibility that mitochondria might integrate and coordinate several functions necessary for erythroid cell maturation prior and during enucleation. To further address mitochondrial functions in terminal erythropoiesis, we will accomplish the following: (Aim 1) we will investigate the contribution of mitochondrial clearance to erythroid cell maturation vs. enucleation; (Aim 2) we will investigate the contribution of mitochondrial network and morphology to the regulation of erythroid cell maturation vs. enucleation, and (Aim 3) we will address the specific pyruvate-mediated pathway that fuel mitochondria during terminal erythropoiesis. These studies are likely to expose a new mechanism of erythroid cell maturation and enucleation and to generate critical information for developing new means towards novel therapies and improving RBC production.

项目概要/摘要 每天 2000 亿个红细胞 (RBC) 的大量产生需要出色的协调 红细胞分化和成熟，以及与红细胞去核有关的过程。 控制终末红细胞成熟和去核的调节机制的改变是 与红细胞和其他疾病有关。对这些过程的了解有限一直是一个障碍 治疗干预和大规模红细胞生产。我们长期以来对转录因子的关注 Foxo3 是终末红细胞生成的中央调节因子，使我们认识到线粒体是关键且重要的。 这些过程中的动态调节器。我们最近表明线粒体正在积极调节 红细胞去核。值得注意的是，我们发现了外源性丙酮酸（糖酵解的产物），但不是原位的 通过糖酵解产生丙酮酸为线粒体提供燃料并维持红细胞去核，这表明 外源丙酮酸在此过程中发挥了意想不到的重要作用。我们正在进行的研究扩展了 这些发现表明，ATP 独立的线粒体功能以及线粒体相关的功能 包括清除在内的途径可能是终末红细胞生成的核心，它们的改变与 疾病。我们的综合研究提出了线粒体可能整合和协调多个 去核前和去核期间红细胞成熟所必需的功能。为进一步解决 为了了解线粒体在终末期红细胞生成中的功能，我们将完成以下任务：（目标 1）我们将研究 线粒体清除率对红细胞成熟与去核的贡献； （目标2）我们将 研究线粒体网络和形态对红细胞调节的贡献 成熟与去核，以及（目标 3）我们将解决特定的丙酮酸介导的途径，该途径促进 红细胞生成终末期的线粒体。这些研究可能揭示红细胞的新机制 细胞成熟和去核，并生成关键信息，用于开发新方法 治疗和改善红细胞生成。