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Integrin-Based Mechanisms in Terminal Erythroid Maturation

基于整合素的红系终末成熟机制

基本信息

批准号：
8875744
负责人：
DAVID E. GOLAN
金额：
$ 41.74万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-26 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8875744
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

项目摘要

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)：在红细胞生成过程中，成熟的红细胞与细胞外基质成分以及与其局部微环境中的其他骨髓细胞形成黏附作用。众所周知，成簇的红细胞依赖于这种相互作用来实现最佳的细胞成熟，但红系微环境在支持和调节红系成熟中的重要作用尚不清楚。细胞膜上的整合素是红细胞细胞-细胞和细胞-基质相互作用的关键介质。除了促进黏附相互作用外，整合素还介导红细胞胞外和胞内环境之间的双向信号传递(由外向内和由内向外)。整合素也是细胞骨架重组的重要媒介，这一过程是红系成熟末期结构变化的核心。在这里，我们建议测量主要的红细胞整合素的膜动力学，定义整合素介导的红细胞黏附相互作用的分子调控，并表征整合素动力学和细胞骨架重组之间的联系。我们还将研究整合素驱动的信号和促红细胞生成素驱动的信号之间的关系，这两个信号可以在稳态和/或应激条件下共同作用以优化红细胞生成。我们的最终目标是了解整合素依赖功能对红细胞生成的影响。我们的实验室非常适合从事这些工作，拥有多种先进的、定量的单分子和单细胞成像技术，以及多色流式细胞术和小鼠模型方面的专业知识。根据我们的初步数据，我们假设红细胞整合素动力学和信号既调节红系成熟又受其支配，整合素介导的事件与促红细胞生成素指导的信号在这一过程中相互作用。在目标1中，我们将描述介绍了成熟红细胞上整合素的膜动力学，阐明了配体参与和细胞骨架重组是如何控制这种动力学的，并阐明了这些动力学对细胞内信号通路的调节。在目标2中，我们将描述调节红系终末成熟的促红细胞生成素依赖通路和整合素依赖通路之间潜在相互作用的机制。该项目的成功完成将为红系发育的潜在机制提供新的见解，并可能有助于确定红细胞生成障碍的治疗干预的新靶点。 (摘要结束)