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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：
8884252
负责人：
Peng Ji
金额：
$ 38.18万
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/8884252
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 Hemolysis In Vitro Knockout Mice Link Lipid Binding Macrocytic Anemia Mediating Mitochondria Modification Mus Oxidative Stress 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 leukemia mouse model novel novel therapeutics phospholipase D1 platelet protein P47 prevent public health relevance 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.

描述（由申请人提供）：过去几十年的研究揭示了促红细胞生成素（Epo）和Rac GTP酶信号通路中的许多关键因素，这些因素对于各种红细胞相关疾病的发展非常重要。然而，许多其他红细胞疾病的发病机制仍不清楚，如先天性红细胞生成障碍性贫血、范可尼贫血、铁粒幼细胞贫血、不明原因的老年人贫血、β地中海贫血无效红细胞生成和骨髓增生异常综合征。这些疾病通常在细胞分化、存活和肌动蛋白动力学方面表现出无法解释的缺陷，这些缺陷模仿了细胞分裂的破坏。 Epo 和/或 Rac GTP 酶途径。然而，迄今为止，尚未报道这些疾病中 Epo 或 Rac GTP 酶途径的直接缺陷。该领域的一个悬而未决的问题是是否存在任何蛋白质或途径连接 Epo 和 Rac GTPase 途径来调节终末红细胞生成，从而可能参与上述疾病的发病机制。在这项工作中，我们发现 pleckstrin-2 (plek2) 通过与丝切蛋白相互作用在红细胞生成终末的不同阶段发挥着关键作用。我们的初步数据和其他小组的报告表明，plek2 与 Epo 和 Rac GTPase 途径密切相关，调节红细胞分化、存活和肌动蛋白动态，形成红细胞生成的全局调节网络。在这个项目中，我们将使用我们完善的小鼠胎儿成红细胞培养系统和各种小鼠模型来确定 plek2 作为体外和体内红细胞生成功能节点的作用。在目标1中，我们将使用表现出大细胞性贫血和胎儿贫血的plek2敲除小鼠模型来确定稳态和应激条件下plek2在体内红细胞生成中的功能。还将使用 Hbbth1/th1 小鼠作为 plek2 的直接红细胞疾病模型来测试 plek2 在 β-地中海贫血发病机制中的作用。在目标 2 中，我们将确定 plek2 受 Epo 信号通路转录或翻译后修饰调节的机制。在目标 3 中，我们将确定 plek2-cofilin 和 Rac GTPase 途径在终末红细胞生成的不同阶段相互需要的程度。这些独立但相互关联的目标的成功实现将揭示 plek2 在调节红细胞生成中的细胞分化、存活和肌动蛋白动态中的核心作用，这可以为病因不明的红细胞相关疾病的发病机制和治疗管理提供新的见解。