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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：
9403199
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/9403199
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 Genetic Diseases Genomics Goals Guanosine Triphosphate Phosphohydrolases Health Hemoglobinopathies 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.

总结