FOXO3 Regulation of Normal and Stress Erythropoiesis

FOXO3 对正常和应激性红细胞生成的调节

基本信息

批准号：
9264330
负责人：
SAGHI GHAFFARI
金额：
$ 42.31万
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 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264330
关键词：
Affect Anemia Anemia due to Chronic Disorder Apoptosis Apoptotic Bone Marrow CD34 gene CDC42 gene Cell Nucleus Cells Chronic Chronic stress Clinical Disease Ectopic Expression Erythroblasts Erythrocytes Erythroid Erythroid Cells Erythropoiesis FOXO3A gene Family member Functional disorder Gene Cluster Genes Genetic Genomics Goals Guanosine Triphosphate Phosphohydrolases Health Hemoglobinopathies Hereditary Disease Human In Vitro Knowledge Mediating Mediator of activation protein Methodology Mitochondria Modeling Mus Nuclear Oxidation-Reduction Oxidative Stress Pathway interactions Pattern Physiological Physiological Processes Polycythemia Vera Population Process Production Property Publishing Regulation Role Side Spleen Stress Testing Therapeutic base beta Thalassemia biological adaptation to stress cell motility design gain of function improved mouse model novel organelle movement quantitative imaging response rho GTP-Binding Proteins transcription factor

项目摘要

SUMMARY Chronic oxidative stress exacerbates an array of erythroid disorders, including hemoglobinopathies, polycythemia vera and anemia of inflammation; yet the mechanisms engaged by erythroid chronic stress- response remain relatively unexplored. In addition, their impact on normal physiological processes is unknown. Our focus has been on the homeostatic transcription factor FOXO3 which is essential for the regulation of the erythropoiesis redox state. We showed recently that FOXO3 is critical for terminal maturation and enucleation in erythropoiesis. On the other hand, our studies indicate that the loss of FOXO3 improves significantly anemia in a model of ß-thalassemia that is a genetic disorder of erythroid cells with redox imbalance at its core. Given the broad scope of FOXO3 functions, the extent of its impact on erythropoiesis may depend on the context. Our overarching goal is to test the hypothesis that chronic activation of FOXO3-mediated stress-response pathways contributes significantly to the deleterious pathophysiology of erythroid disorders. To test this hypothesis we propose to employ novel quantitative imaging methodologies, genomic high-throughput approaches, and in vitro cultures of human erythroblasts and mouse models generated on pure genetic background combined with loss- and gain-of-function approaches to achieve the following independent yet highly complementary and synergistic aims: (Aim 1): To investigate mechanisms whereby FOXO3 regulates erythroblast enucleation; (Aim 2): To elucidate the role of FOXO3 in β-thalassemic erythropoiesis. These combined studies will elucidate how chronic activation FOXO3-mediated stress response may alter normal physiological processes and aggravate β-thalassemia specifically and more broadly erythroid disorders.

概括慢性氧化应激会加重一系列红细胞疾病，包括血红蛋白病、真性红细胞增多症和炎症性贫血；但红细胞慢性应激所涉及的机制此外，它们对正常生理过程的影响尚不清楚。未知。我们的重点是稳态转录因子 FOXO3，它对于生命活动至关重要。我们最近表明 FOXO3 对于终末期红细胞生成氧化还原状态至关重要。另一方面，我们的研究表明红细胞生成的成熟和去核。 FOXO3 显着改善 β 地中海贫血（一种红细胞遗传性疾病）模型中的贫血鉴于 FOXO3 功能的广泛性，其影响的程度。对红细胞生成的影响可能取决于具体情况。我们的首要目标是检验慢性的假设。 FOXO3介导的应激反应途径的激活显着促进有害的为了检验这一假设，我们建议采用新的定量方法。成像方法、基因组高通量方法以及人成红细胞的体外培养以及在纯遗传背景下生成的具有功能丧失和功能获得相结合的小鼠模型实现以下独立但高度互补和协同目标的方法：（目标 1）：研究 FOXO3 调节红细胞去核的机制（目标 2）：阐明 FOXO3 在 β-地中海贫血性红细胞生成中的作用这些联合研究将阐明。 FOXO3 介导的慢性激活应激反应如何改变正常的生理过程以及特别加重β-地中海贫血，更广泛地加重红细胞疾病。