Mitochondria in the Regulation of Terminal Erythropoiesis

线粒体对终末红细胞生成的调节

基本信息

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
项目类别：
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

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

展开

项目摘要

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.

项目摘要/摘要每日大量生产2000亿红细胞（RBC）需要显着协调红细胞细胞分化和成熟，并具有在红细胞启用中实现的过程。控制末端红细胞成熟和枚举的调节机制的改变是在红细胞和其他疾病中实施。对这些过程的了解有限是一种障碍用于治疗干预措施和大规模的RBC生产。我们长期关注转录因子 FOXO3是终端红霉病的中心调节剂，使我们确定线粒体是关键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壳细胞。值得注意的是，我们发现了外源丙酮酸 - 糖酵解的产物 - 但没有原位通过糖酵解燃料线粒体和自杀的红合作生产的丙酮酸枚举表明在此过程中，外源性丙酮酸的意外功能和重要功能。我们正在进行的研究扩展了这些发现，并表明与ATP无关的线粒体功能以及线粒体相关包括清除在内的途径可能是终端红细胞生成的核心及其在疾病。我们的合并研究提出了线粒体可能整合并协调几个的可能性围栏之前和期间，红细胞成熟所需的功能。进一步解决线粒体功能在终端红细胞生成中，我们将完成以下操作：（ AIM 1）我们将调查线粒体清除对红细胞细胞成熟的贡献与枚举；（目标2）我们将研究线粒体网络和形态对红细胞细胞调节的贡献成熟与枚举，（目标3）我们将解决燃料燃料的特定丙酮酸介导的途径线粒体末端红细胞生成。这些研究可能会揭示红斑的新机制细胞成熟和枚举，并生成关键信息，以开发新的手段治疗和改善RBC生产。