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：
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
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/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

项目摘要

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 (GTPases) Rac1 和 Rac2 调节多种细胞类型中的肌动蛋白细胞骨架、微管动力学、基因转录、增殖和存活。它们已被证明在各种造血细胞谱系的肌动蛋白组织、细胞存活和增殖中具有重叠和独特的作用。然而，它们在红细胞前体和红细胞中的作用尚未得到评估。使用基因靶向小鼠，我们发现 Rac1 和 Rac2 GTPases 缺陷会导致红细胞谱系出现显着的表型：轻度贫血伴相对网织红细胞增多，本质上是溶血性贫血（红细胞骨架结构异常，机械稳定性下降）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）发挥着关键作用。因此，我们假设 Rac GTPases (1) 动态调节红细胞骨架的结构和功能，(2) 在红细胞前体细胞的归巢、增殖、存活和分化中发挥关键作用，可能与通过 SCF 受体激活的信号通路相交叉，c-套件。为了检验我们的假设，我们提出系统表征 Rac GTPase 缺陷对 RBC 细胞骨架中肌动蛋白聚合机制的影响，分析肌动蛋白相关蛋白并评估 Rac 与其他 Rho GTPase 和信号传导可能的串扰分子。与此同时，我们将研究 Rac1"/";Rac2"/" 小鼠中红细胞生成的扰动，寻找 Rac GTPases 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。这两个提出的目标旨在探索和测试 Rac GTPases 如何调节红细胞发育、形态发生以及红细胞骨架及其成分的结构功能关系。中心目标是定义参与正常红细胞发育和红细胞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。（摘要完）