Integrin-Based Mechanisms in Terminal Erythroid Maturation

基于整合素的红系终末成熟机制

• 批准号: 8677968
• 负责人: DAVID E. GOLAN
• 金额: $ 41.53万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677968
• 关键词: Adhesions; Adhesives; Anemia; Bone Marrow; Bone Marrow Cells; Bone Marrow Diseases; Cell Maturation; Cell membrane; Cell surface; Cells; Chronic Kidney Failure; Cytoskeletal Modeling; Data; Development; Disease; Environment; Erythroblasts; Erythrocytes; Erythroid; Erythropoiesis; Erythropoietin; Event; Extracellular Matrix; Flow Cytometry; Goals; Hematopoietic; Hematopoietic stem cells; Human; Imaging Techniques; Integrins; Laboratories; Lateral; Lead; Ligands; Ligation; Link; Measures; Mediating; Mediator of activation protein; Membrane; Molecular; Movement; Mus; Pathway interactions; Process; Proliferating; Receptor Cell; Regulation; Research; Role; Signal Pathway; Signal Transduction; Site; Staging; Stress; Techniques; Therapeutic Intervention; Therapeutic Uses; Whole Organism; Work; abstracting; base; biophysical properties; cellular imaging; effective therapy; extracellular; improved; insight; mouse model; novel; single molecule

DESCRIPTION (provided by applicant): During erythropoiesis, maturing erythroblasts form adhesive interactions with extracellular matrix components and with other bone marrow cells in their local microenvironment. It is known that clusters of erythroblasts rely on such interactions for optimal cell maturation, but the precie role of the erythropoietic microenvironment in supporting and modulating erythroid maturation is unclear. Integrins in the cell membrane are the key mediators of erythroblast cell-cell and cell-matrix interactions. In addition to promoting adhesion interactions, integrins mediate bidirectional signaling (outside-in and inside-out) between the extracellular and intracellular environments of the erythroblast. Integrins are also important mediators of cytoskeletal reorganization, a process that is central to the structural changes occurring in the terminal stages of erythroid maturation. Here, we propose to measure the membrane dynamics of the major erythroblast integrins, define the molecular regulation of integrin-mediated erythroblast adhesion interactions, and characterize the links between integrin dynamics and cytoskeletal reorganization. We will also investigate the relationship between integrin-driven signaling and erythropoietin-driven signaling, which could work together to optimize erythropoiesis under homeostatic and/or stress conditions. Our ultimate goal is to understand the impact of integrin-dependent functions on erythropoiesis. Our laboratory is ideally suited to undertake these endeavors, having at our disposal multiple advanced, quantitative single-molecule and single-cell imaging techniques as well as expertise in multicolor flow cytometry and mouse models. Based on our preliminary data, we hypothesize that erythroblast integrin dynamics and signaling both modulate and are governed by erythroid maturation and that integrin-mediated events interact with erythropoietin-directed signaling in this process. In Aim 1, we will characterize the membrane dynamics of integrins on the maturing erythroblast, define how such dynamics are controlled by ligand engagement and cytoskeletal reorganization, and elucidate the regulation of intracellular signaling pathways by these dynamics. In Aim 2, we will characterize mechanisms of potential interaction between erythropoietin-dependent pathways and integrin-dependent pathways that regulate terminal erythroid maturation. Successful completion of this project will provide new insights into the mechanisms underlying erythroid development and may aid in the identification of novel targets for therapeutic intervention in disorders of erythropoiesis. (End of Abstract)

描述（由申请人提供）： 在红细胞生成期间，成熟的红细胞与细胞外基质成分以及其局部微环境中的其他骨髓细胞形成粘合剂相互作用。众所周知，红细胞的簇依赖于这种相互作用来最佳细胞成熟，但是红细胞生成微环境在支撑和调节红细胞成熟方面的precie作用尚不清楚。细胞膜中的整联蛋白是红细胞细胞 - 细胞和细胞基质相互作用的关键介体。除了促进粘附相互作用之外，整联蛋白还介导了红细胞的细胞外和细胞内环境之间的双向信号（外部和内部）。整联蛋白也是细胞骨架重组的重要介体，这一过程对于在红斑成熟的末端阶段发生的结构变化至关重要。在这里，我们建议测量主要成红细胞整合素的膜动力学，定义整联蛋白介导的成年细胞粘附相互作用的分子调节，并表征整合素动力学与细胞骨架重组之间的联系。我们还将调查整联蛋白驱动的信号传导与促红细胞生成素驱动的信号之间的关系，这些信号传导可以共同起作用，以优化稳态和/或应力条件下的红细胞生成。我们的最终目标是了解整合素依赖性功能对红细胞生成的影响。我们的实验室非常适合进行这些努力，并具有多种高级，定量的单分子和单细胞成像技术以及多色流式细胞仪和小鼠模型的专业知识。基于我们的初步数据，我们假设红细胞整合素动力学和信号传导既调节又由红细胞的成熟来控制，并且整联蛋白介导的事件在此过程中与促红细胞生成素的信号相互作用。在AIM 1中，我们将表征 整联蛋白在成熟的成年细胞上的膜动力学定义了如何通过配体参与和细胞骨架重组来控制这种动力学，并通过这些动力学阐明了细胞内信号通路的调节。在AIM 2中，我们将表征促红细胞生成素依赖性途径与整合素依赖性途径之间的潜在相互作用的机制，这些途径调节了末端红斑成熟。该项目的成功完成将提供有关红细胞发育基础机制的新见解，并可能有助于确定红细胞生成疾病的治疗干预措施的新靶标。 （抽象的结尾）