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Rac1 and Rac2 Guanosine Triphosphatases in Erythroid Function and Differentiation

Rac1 和 Rac2 鸟苷三磷酸酶在红细胞功能和分化中的作用

基本信息

批准号：
8197491
负责人：
Theodosia Anastasios Kalfa
金额：
$ 12.87万
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：
2008
资助国家：
美国
起止时间：
2008-02-11 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197491
关键词：
Actins Adhesions Affect Anemia Apoptosis Biological Assay Bone Marrow Cell Cycle Cell Lineage Cell Nucleus Cell Polarity Cell Survival Cells Cytoskeletal Proteins Cytoskeleton Data Defect Development Erythroblasts Erythrocyte Deformability Erythrocyte Membrane Erythrocytes Erythroid Erythroid Cells Erythropoiesis Evaluation F-Actin Flow Cytometry Gene Targeting Genetic Transcription Goals Growth Factor Receptors Guanosine Guanosine Triphosphate Phosphohydrolases Hematopoietic Hematopoietic stem cells Hemolytic Anemia Homing In Vitro Label Mammals Mechanics Mediating Membrane Biology Microtubules Molecular Morphogenesis Movement Mus Nature Pathogenesis Pathway interactions Phenotype Phosphorylation Play Poikilocytosis Population Process Protein Kinase C Proteins Proto-Oncogene Protein c-kit Regulation Relative (related person)Research Reticulocytes Reticulocytosis Rho-associated kinase Role Signal Pathway Signal Transduction Signaling Molecule Spectrin Spleen Staging Stem Cell Factor Stress Structure Testing Tropomyosin adducin cell type cofilin cytokine erythroid differentiation extracellular human disease in vitro Assay in vivo microcytic anemia polymerization rac GTP-Binding Proteins response rho therapeutic target tropomodulin

项目摘要

The Rho guanosine triphosphatases (GTPases) Rac1 and Rac2 regulate actin cytoskeleton, microtubule dynamics, gene transcription, proliferation, and survival in multiple cell types. They have been shown to have overlapping as well as distinct roles in actin organization, cell survival, and proliferation in various hematopoietic cell lineages. However their role in erythroid precursors and erythrocytes has not been evaluated. Using gene-targeted mice we have found that deficiency of Rac1 and Rac2 GTPases causes a significant phenotype in erythroid lineage: mild anemia with relative reticulocytosis, both hemolytic (abnormal structure of the erythrocyte cytoskeleton with decreased mechanical stability) and dyserythropoietic in nature. Erythropoiesis is affected mainly at the early stages, when stem cell factor (SCF) plays a critical role. We therefore hypothesize that Rac GTPases (1) dynamically regulate the structure and function of the erythrocyte cytoskeleton, and (2) play a critical role in homing, proliferation, survival, and differentiation of erythroid precursors, likely intersecting signaling pathways activatedvia the SCF receptor, c-Kit. To test our hypotheses, we propose a systematic characterization of the effects of Rac GTPase deficiency on the actin polymerization mechanics in the RBC cytoskeleton, with analysis of the actin-associated proteins and evaluation of possible cross-talk of Rac with other Rho GTPases and signaling molecules. In parallel, we will investigate the perturbations of erythropoiesis in Rac1"/";Rac2"/" mice, seeking the mechanism/s by which Rac GTPases, integrating multiple signals from one or more of the erythropoietic cytokines, affect erythropoiesis. These two proposed aims intent to explore and test how Rac GTPases regulate erythroid development, morphogenesis, and structure-function relation of the RBC cytoskeleton and its components. The central goal is to define critical molecular signaling pathways that participate in normal erythroid development and RBC structural membrane biology. In the long-term, this research is expected to offer new perspectives on the pathogenesis of hemolytic anemia and provide potential therapeutic targets in human disease characterized by abnormal erythropoiesis and decreased RBC survival.

Rho鸟苷三磷酸酶(GTP酶)rac1和rac2调节肌动蛋白细胞骨架，多种细胞类型中的微管动力学、基因转录、增殖和存活。他们一直都是在肌动蛋白的组织、细胞存活和增殖中具有重叠和不同的作用各种造血细胞谱系。然而，它们在红系前体和红细胞中的作用并没有已经评估过了。利用基因靶向的小鼠，我们发现了rac1和rac2 GTP酶的缺乏导致红系的显著表型：轻度贫血伴相对网织红细胞增多症，两者溶血性(红细胞细胞骨架结构异常，机械稳定性降低)和在自然界中具有促红细胞生成功能。红细胞生成主要在早期阶段受到影响，当干细胞因子 (SCF)起着至关重要的作用。因此，我们假设RAC GTP酶(1)动态调节红细胞细胞骨架的结构和功能，以及(2)在归巢、增殖、红系前体的存活和分化，可能通过激活的信号通路相交干细胞因子受体，c-Kit。为了检验我们的假设，我们提出了一个系统的描述 RAC GTPase缺失对红细胞细胞骨架肌动蛋白聚合机制的影响肌动蛋白相关蛋白及Rac与其他Rho GTP酶和Rho GTP酶之间可能的相互作用信号分子。同时，我们将研究在rac1“/”；rac2“/”中的红细胞生成的扰动。小鼠，寻找Rac GTP酶的机制/S，整合来自一个或多个促红细胞生成的细胞因子会影响红细胞的生成。这两个提议的目标意在探索和测试 Rac GTP酶调节红系发育、形态发生和结构-功能关系细胞骨架及其组成部分。中心目标是定义参与正常红系的关键分子信号通路。发育与红细胞结构膜生物学。从长远来看，这项研究有望提供溶血性贫血发病机制的新视角及潜在的治疗靶点一种以异常的红细胞生成和红细胞存活率降低为特征的人类疾病。