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Rho GTPases in Terminal Erythroid Maturation

红细胞终末成熟中的 Rho GTP 酶

基本信息

批准号：
8685320
负责人：
Theodosia Anastasios Kalfa
金额：
$ 37.49万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-26 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8685320
关键词：
Actins Actomyosin Adhesions Anemia BFU-E Binding Biochemical Breeding CFU-E Cell Nucleus Cell Polarity Cells Chronic Colchicine Cytokinesis Cytoskeletal Proteins Cytoskeleton Data Daughter Defect Development Disease Dysmyelopoietic Syndromes Erythroblasts Erythrocyte Membrane Erythrocytes Erythroid Erythroid Cells Erythropoiesis Excision Extracellular Matrix F-Actin Family member Fetal Liver Figs - dietary GTP Binding Genetic Goals Guanosine Triphosphate Phosphohydrolases Hematopoietic In Situ In Vitro Inflammatory Integrins Investigation Island LIMK1 gene Mammals Mediating Membrane Microdomains Microtubule Polymerization Microtubules Modeling Molecular Mus Myosin Type II Neoplasms Pathway interactions Play Poikilocytosis Polyploidy Process Production Protocols documentation Rattus Regulation Reticulocytes Role Safety Signal Transduction Speed Staging Surface Testing Thalassemia Therapeutic Intervention Time Transfusion Transplantation Tubulin Vascular blood supply Work abstracting anillin base bone cellular imaging citron rho-interacting kinase cofilin constriction daughter cell erythroid differentiation improved in utero in vivo macrophage non-muscle myosin novel polymerization profilin progenitor receptor reconstitution rho GTP-Binding Proteins

项目摘要

DESCRIPTION (provided by applicant): Terminal differentiation within the erythroid lineage in mammals concludes with the dramatic process of enucleation that results in reticulocyte formation. The interactions of erythroblasts with macrophages within the erythroblastic islands are critical for efficient enucleation. Defects in the final stages of erythropoiesis are common causes of anemia in chronic inflammatory diseases and neoplasia and in many primary hematological processes, like myelodysplasia and thalassemia. Limited understanding of the mechanisms involved in terminal erythroid maturation impedes development of novel therapies for such diseases. Using a novel analysis protocol of multiparameter high-speed cell imaging in flow we demonstrated evidence that enucleation is a multi-step process resembling asymmetric cytokinesis. It requires establishment of cell polarity through microtubule function, followed by formation of a contractile actomyosin ring, and coalescence of lipid rafts between reticulocytes and pyrenocytes. Moreover, we showed that Rac GTPases organize actin in the actomyosin ring and aggregate lipid rafts in the furrow between nascent reticulocyte and pyrenocyte during enucleation. RhoA GTPase is known to play a significant role in cytokinesis and abscission of the daughter cells. Based on the resemblances between erythroblast enucleation and cytokinesis we hypothesize that Rac and RhoA dynamically control erythroblast enucleation by intrinsic molecular pathways analogous to the ones conducting cytokinesis. Based on the critical role of erythroblast-macrophage interaction for efficient erythropoiesis and the known function of Rac and RhoA in signaling initiated by integrins we hypothesize that Rac and RhoA transduce critical macrophage signals to the erythroblasts, regulating terminal erythroid differentiation and enucleation within the erythroblastic islands. To define the mechanistic contribution of RhoA signaling and the relationship of RhoA/Rac in regulating actin and microtubule cytoskeleton in the final stages of erythropoiesis, we bred mice with erythroid specific deletion (EpoRGFPcre/+ driven) of RhoA and Rac1/Rac2/Rac3. To test our hypotheses, we propose in Aim 1 to define the molecular processes by which RhoA/Rac-regulated cytoskeleton dynamics contribute to erythroblast enucleation and in Aim 2 to determine the role of Rho GTPases in enucleation and erythroblast maturation within erythroblastic islands. The goal of this proposal is to investigate the intracellular and intercellular molecular mechanisms by which Rac and RhoA regulate erythroblast differentiation and enucleation via dynamic regulation of actin and microtubule cytoskeletons. This study has the potential to reveal targets for in vivo therapeutic intervention for anemias due to terminal erythroid maturation defects as well as for improving the efficiency of red blood cell production in vitro. (End of Abstract)

描述（由申请人提供）：