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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：
10754310
负责人：
Stefano Di Talia
金额：
$ 6.74万
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/10754310
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 Cytoskeleton 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 Population Primordium Process Proliferating Protein Analysis Publishing Regenerative capacity Regulation Risk Signal Transduction Skeletal bone Skin Structure System Testing Tissues Transgenic Organisms Trauma Travel Work Zebrafish bone bone imaging cell behavior craniofacial development economic impact experimental study genetic approach imaging modality imaging platform improved in vivo imaging insight limb amputation live cell imaging mathematical model member migration novel pharmacologic programs regeneration potential regenerative growth response single cell sequencing socioeconomics spatiotemporal transcription factor transcriptome transcriptomic profiling transmission process

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.

摘要哺乳动物的骨骼在整个生命过程中都具有响应骨折损伤而再生的能力。是这种再生潜力的上限，在肢体等重大创伤后再生障碍截肢。这具有重大的社会经济影响，因为据估计，预计50岁以上的人患有或有患骨病的风险，每年估计有150万人最近，我们已经开发出成像方法来研究如何成骨细胞驱动斑马鱼的骨再生，在骨损伤后显示出强大的再生能力。我们的目标是利用这种再生能力，新的成像技术，我们已经创建的平台，以及在斑马鱼中可用的分子遗传方法，了解和操纵骨的再生能力。这项建议的目标是产生一种在骨再生能力的基础上，我们的实验将测试再生模式化骨骼的细胞和信号事件。假设再生骨的正确模式需要动态信号事件，成骨细胞行为的个体和群体水平。 1）我们将使用长期的实时成像，标记光生物可转换蛋白质，以及计算机分析，以生成细胞增殖的详细地图，肥大和细胞流动，以及与邻近组织的相互作用驱动骨再生。2）我们将使用尖端的生物传感器，实时成像，计算方法和数学建模来解剖化学信号的行波如何刺激再生成骨细胞群体的生长。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力学，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这些实验将定义一个新的定量框架，用于了解成骨细胞如何行为协调骨再生。