权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The roles of pleckstrin-2 as a functional node in erythropoiesis

pleckstrin-2 作为红细胞生成功能节点的作用

基本信息

批准号：
9052762
负责人：
Peng Ji
金额：
$ 36.09万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-10 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9052762
关键词：
1-Phosphatidylinositol 3-Kinase Actins Affect Anemia Apoptosis Binding Binding Proteins Biological Assay Cell Death Cell Differentiation process Cell surface Cells Cellular Structures Congenital dyserythropoietic anemia Cytoskeleton Data Data Reporting Defect Development Disease Disease Management Disease model Dysmyelopoietic Syndromes Elderly Erythroblasts Erythrocytes Erythroid Erythroid Cells Erythropoiesis Erythropoietin Etiology Exhibits Fanconi&apos s Anemia Feedback Fetal Liver Functional disorder Goals Guanosine Triphosphate Phosphohydrolases Health Hemolysis In Vitro Knockout Mice Link Lipid Binding Macrocytic Anemia Mediating Mitochondria Modification Mus Oxidative Stress PI3 gene Pathogenesis Pathway interactions Play Post-Translational Protein Processing Proteins Publishing Regulation Reporting Research Role Series Sideroblastic Anemia Signal Pathway Signal Transduction Staging Stress System Testing Therapeutic Transcriptional Regulation Translational Regulation Transplantation Work beta Thalassemia cofilin cofilin 2 fetal in vitro testing in vivo insight knock-down leukemia mouse model novel novel therapeutics phospholipase D1 platelet protein P47 prevent receptor

项目摘要

DESCRIPTION (provided by applicant): Research in the past few decades has revealed many key factors in erythropoietin (Epo) and Rac GTPase signaling pathways that are important for the development of various red blood cell related diseases. However, the pathogenesis of many other erythroid disorders, such as congenital dyserythropoietic anemias, Fanconi anemia, sideroblastic anemia, unexplained anemia of the elderly, ineffective erythropoiesis in beta-thalassemia, and myelodysplastic syndromes, remain unclear. These diseases often show unexplained defects in cell differentiation, survival, and actin dynamics that mimic disruptions of Epo and/or Rac GTPase pathways. However, no direct defects in Epo or Rac GTPase pathways have been reported to date in these diseases. An open question in the field is whether there are any proteins or pathways that link Epo and Rac GTPase pathways to regulate terminal erythropoiesis, which could be involved in the pathogenesis of aforementioned diseases. In this effort, we discovered that pleckstrin-2 (plek2) plays a critical role in different stages of terminl erythropoiesis through the interaction with cofilin. Our preliminary data and reports from other groups indicated that plek2 is closely interrelated with Epo and Rac GTPase pathways to regulate erythroid cell differentiation, survival and actin dynamics to form a global regulatory network in erythropoiesis. In this project, we will determine the roles of plek2 as a functional node in erythropoiesis in vitro and in vivo using our well-established mouse fetal erythroblast culture system and various mouse models. In Aim 1, we will use plek2 knockout mouse model, which showed macrocytic anemia and fetal anemia, to determine the functions of plek2 in erythropoiesis in vivo under steady state and stress conditions. The role of plek2 in the pathogenesis of beta-thalassemia will also be tested using Hbbth1/th1 mice as a direct red cell disease model for plek2. In Aim 2, we will determine the mechanisms by which plek2 is regulated by Epo signaling pathways transcriptionally or through post-translational modifications. In Aim 3, we will determine the extent to which plek2-cofilin and Rac GTPase pathways are reciprocally required in different stages of terminal erythropoiesis. Successful accomplishment of these independent but interconnected aims will reveal a central role of plek2 in regulating cell differentiation, survival and actin dynamics in erythropoiesis, which could provide novel insights into the pathogenesis and therapeutic management of red cell related diseases with unclear etiology.