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LIVE IMAGING OF BONE REGENERATION IN ZEBRAFISH

斑马鱼骨再生的实时成像

基本信息

批准号：
10324550
负责人：
Stefano Di Talia
金额：
$ 51.52万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10324550
关键词：
Adult Age American Automobile Driving Behavior Biography Biosensor Bone Diseases Bone Matrix Bone Regeneration Cell Proliferation Cell division Cells Cessation of life Chemicals Clinical Competence Complement Complex Computer Analysis Data Set Daughter Dermal Embryo Epithelial Cells Event Extracellular Signal Regulated Kinases FGF12 gene Fracture Gene Expression Genes Genetic Genetic Transcription Goals Growth Growth Factor Heterogeneity Hypertrophy Image Individual Injury Jaw Label Laboratories Life Ligands Limb structure Link Maps Mediating Messenger RNA Methodology Methods Mitogens Modeling Molecular Molecular Genetics Monitor Morphogenesis Natural regeneration Osteoblasts Osteoclasts Pathway interactions Pattern Pharmacology Population Primordium Process Protein Analysis Publishing Regenerative capacity Regulation Risk Signal Transduction Skeletal bone Skin Structure System Testing Tissues Transgenic Organisms Trauma Travel Work Zebrafish base bone bone imaging cell behavior craniofacial development experimental study genetic approach imaging modality imaging platform improved in vivo imaging insight limb amputation live cell imaging mathematical model member migration novel programs regeneration potential regenerative growth response single cell sequencing socioeconomics spatiotemporal transcription factor transcriptome

项目摘要

Abstract Mammalian bone has the capacity throughout life to regenerate in response to fracture injury. However, there is a ceiling for this regenerative potential, with hurdles to regeneration after a major trauma like limb amputation. This has a significant socioeconomic impact, as it is estimated that at least one in two Americans over age 50 is expected to have or be at risk of bone disease, and every year an estimated 1.5 million individuals suffer a fracture due to bone disease. Recently, we have developed imaging methods to study how osteoblasts drive bone regeneration in zebrafish, which display robust regeneration after major injury to bony structures like their fins, scales, and jaws. Our goal is to exploit this regenerative capacity, new imaging platforms we have created, and the molecular genetic approaches available in zebrafish to improve our ability to understand and manipulate the regenerative capacity of bone. The goal of this proposal is to generate an in toto map of the cellular and signaling events that regenerate patterned skeletal bone. Our experiments will test the hypothesis that correct patterning of regenerating bone requires dynamic signaling events that control osteoblast behaviors at individual and population levels. 1) We will use long-term live imaging, labeling with photo-convertible proteins, and computational analysis to generate a detailed map of how cell proliferation, hypertrophy and cellular flows, and interactions with neighboring tissues drive bone regeneration. 2) We will use cutting edge biosensors, live imaging, computational approaches, and mathematical modeling to dissect how traveling waves of chemical signals stimulate the growth of a regenerating osteoblast population. 3) We will use transcriptome profiling approaches to derive further insights on the dynamics of growth factor signaling, including single-cell sequencing-based approaches to link gene expression programs with osteoblast behaviors. These experiments will define a novel quantitative framework for understanding how osteoblast behaviors orchestrate bone regeneration.

抽象的哺乳动物的骨骼在整个生命过程中都具有再生能力，以应对骨折损伤。然而，有是这种再生潜力的上限，在肢体等重大创伤后再生存在障碍截肢。这具有重大的社会经济影响，因为据估计，至少有二分之一的美国人 50 岁以上预计患有骨病或面临骨病风险，每年估计有 150 万人个人因骨病而遭受骨折。最近，我们开发了成像方法来研究如何成骨细胞驱动斑马鱼的骨再生，斑马鱼在骨严重损伤后表现出强劲的再生能力结构，如鳍、鳞片和下巴。我们的目标是利用这种再生能力，新的成像我们创建的平台以及斑马鱼中可用的分子遗传方法可以提高我们的能力了解和操纵骨骼的再生能力。该提案的目标是产生一个再生图案骨骼的细胞和信号事件的托托图。我们的实验将测试假设正确的再生骨骼模式需要控制动态信号事件个体和群体水平的成骨细胞行为。 1) 我们将使用长期实时成像，并用光转换蛋白质，以及计算分析，以生成细胞如何增殖的详细图谱，肥大和细胞流动以及与邻近组织的相互作用驱动骨骼再生。 2) 我们会使用尖端生物传感器、实时成像、计算方法和数学建模来剖析化学信号的行波如何刺激再生成骨细胞群的生长。 3) 我们将使用转录组分析方法来进一步了解生长因子信号传导的动态，包括基于单细胞测序的方法，将基因表达程序与成骨细胞联系起来行为。这些实验将定义一个新颖的定量框架，用于理解成骨细胞如何行为协调骨骼再生。