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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：
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
项目类别：
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

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）：