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

• 批准号: 7385302
• 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
• 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/7385302
• 关键词: Actins; Adhesions; Affect; Anemia; Apoptosis; Biological Assay; Bone Marrow; Cell Cycle; Cell Lineage; Cell Nucleus; Cell Polarity; Cell Survival; Cells; Classification; 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; abstracting; adducin; cell type; cofilin; cytokine; erythroid differentiation; extracellular; granulocyte; human disease; in vitro Assay; in vivo; microcytic anemia; polymerization; rac GTP-Binding Proteins; response; rho; rho GTP-Binding Proteins; therapeutic target; tropomodulin

DESCRIPTION (provided by applicant): 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 activated via 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. (End of Abstract)

描述（由申请人提供）： Rho鸟苷三磷酸酶（GTP酶）Rac 1和Rac 2调节肌动蛋白细胞骨架、微管动力学、基因转录、增殖和多种细胞类型中的存活。它们已被证明在各种造血细胞谱系中的肌动蛋白组织、细胞存活和增殖中具有重叠以及不同的作用。然而，其在红细胞前体和红细胞中的作用尚未得到评价。使用基因靶向小鼠，我们发现Rac 1和Rac 2 GTP酶的缺乏导致红细胞谱系中的显著表型：轻度贫血伴相对网织红细胞增多症，溶血性（红细胞细胞骨架结构异常，机械稳定性降低）和红细胞生成障碍。红细胞生成主要在早期阶段受到影响，此时干细胞因子（SCF）起着关键作用。因此，我们假设Rac GTP酶（1）动态调节红细胞骨架的结构和功能，（2）在红细胞前体的归巢、增殖、存活和分化中起关键作用，可能与通过SCF受体c-Kit激活的信号通路交叉。为了验证我们的假设，我们提出了一个系统的表征的影响，Rac GTPases缺乏对肌动蛋白聚合力学在RBC细胞骨架，肌动蛋白相关蛋白的分析和评估可能的串扰Rac与其他Rho GTPases和信号分子。与此同时，我们将研究Rac 1”/"; Rac 2”/”小鼠中红细胞生成的扰动，寻找Rac GTP酶整合来自一种或多种红细胞生成细胞因子的多种信号影响红细胞生成的机制。这两个目的旨在探索和测试Rac GTP酶如何调节红细胞发育、形态发生以及红细胞骨架及其组分的结构-功能关系。中心目标是确定参与正常红细胞发育和RBC结构膜生物学的关键分子信号传导途径。从长远来看，这项研究有望为溶血性贫血的发病机制提供新的视角，并为以红细胞生成异常和红细胞存活率降低为特征的人类疾病提供潜在的治疗靶点。 (End摘要）