New transgenic tools for mammalian fibrosis and regenerative repair research

用于哺乳动物纤维化和再生修复研究的新转基因工具

基本信息

批准号：
9331056
负责人：
Kathleen Joyce Millen
金额：
$ 27.49万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-15 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9331056
关键词：
Acomys Adult Age Aging Alleles Animal Experimentation Animals Area Biological Models Biology Biomedical Research Biosensor CRISPR/Cas technology Cartilage Cell Cycle Cell Line Cells Chronic Cicatrix Clustered Regularly Interspaced Short Palindromic Repeats Communities Comparative Study Cyclic AMP-Dependent Protein Kinases DNA sequencing Data Development Distant Ear Employee Strikes Epidermis Extracellular Matrix Failure Female Fibroblasts Fibrosis Fluorescence Functional disorder Gene Expression Genetic Genome Genomics Goals Habitats Healthcare Homeostasis Human Inflammatory Injectable Injury Kidney Kinetics Knock-in Label MAPK14 gene Mammals Maps Measures Mediating Modeling Molecular Mus Natural regeneration Nature Nervous system structure Neuraxis Nuclear Oocytes Organ Output Pathologic Pathway interactions Phosphotransferases Poikilotherms Population Predatory Behavior Production Property Proto-Oncogene Proteins c-akt Regenerative Medicine Regulation Reporter Reporting Research Resources Rodent Rodent Model Signal Pathway Signal Transduction Signal Transduction Pathway Skin Skin wound Structure Subfamily lentivirinae System Technology Tissues Transgenic Animals Transgenic Organisms Translating Transplantation Validation Wound Healing Wounds and Injuries base blastocyst cytokine design design and construction embryonic stem cell experimental study fascinate genetic manipulation healing human disease innovation insight novel offspring programs recombinase-mediated cassette exchange regenerative repaired reproductive reproductive fitness response response to injury screening skin regeneration tool vector

项目摘要

PROJECT SUMMARY Our goal is to develop Acomys cahirinus as a new alternative mammalian model system, since they represent the only known mammalian species that retains a remarkable capacity for increased regenerative healing potential across multiple systems as adults. As mammals, the molecular pathways for regenerative repair in Acomys are unique, yet are not likely to be distant from those required for human therapy. Although Acomys may be the best key for unlocking our own capacity for regeneration and untangling the relationship between homeostatic repair versus pathological fibrosis in mammals, Acomys animals for research purposes are more stringently regulated than other rodent models, and hence are currently in limited use in biomedical research. Our innovative approach to enable rapid research across multiple systems has been to first sequence, assemble and annotate a high quality Acomys cahirinus Genomic Resource. Our second step is to develop Acomys Cell and Transgenic Resources to more rapidly facilitate their utilization in biomedical research. Our multipisciplinary Acomys Research Team has extensive evidence that cells from different adult Acomys tissues grow surprisingly well in primary cultures. In fact, isolated Acomys fibroblasts actively resist cytokine-mediated myofiboblast induction by both changing gene expression and by differentially regulating signal transduction kinetics in homeostatic and regenerative pathways. We propose to develop Acomys cell lines from multiple adult tissues, genetically encode them with an array of fluorescent biosensor tools that report activity of key signaling pathways, generating essential tools to unravel the important mechanistic details of Acomys regenerative biology. We also aim to develop transgenic Acomys technology and animals to rapidly facilitate use of these remarkable animals by the broader scientific community. We believe that enabling access and facilitating research into this fascinating experiment of nature offers truly novel possibilities for discovery with far-reaching implications for human regenerative medicine.

项目摘要我们的目标是将Acomys Cahirinus作为一种新的替代哺乳动物模型系统，因为它们代表唯一已知的哺乳动物物种，具有出色的再生愈合能力作为成年人的多个系统的潜力。作为哺乳动物，用于再生修复的分子途径 ACOMYS是独一无二的，但不可能与人类治疗所需的相距甚远。虽然是Acomys 可能是解锁我们自身再生能力并解开之间关系的最佳关键哺乳动物的稳态维修与病理纤维化，用于研究目的的Acomys动物更多比其他啮齿动物模型受到严格调节，因此目前在生物医学研究中使用有限。我们在多个系统之间进行快速研究的创新方法是第一序列，组装和注释高质量的Acomys Cahirinus基因组资源。我们的第二步是发展 Acomys细胞和转基因资源更快地促进了它们在生物医学研究中的利用。我们的多学科ACOMYS研究团队有广泛的证据表明来自不同成人Acomys组织的细胞在初级文化中出人意料地成长。实际上，孤立的ACOMYS成纤维细胞积极抗拒细胞因子介导通过改变基因表达和通过差异调节信号转导的肌纤维细胞诱导稳态和再生途径的动力学。我们建议从多个成人组织，用一系列荧光生物传感器工具对它们进行遗传编码，以报告钥匙的活动信号通路，生成基本工具来揭示Acomys的重要机理细节再生生物学。我们还旨在开发转基因Acomys技术和动物，以迅速促进更广泛的科学界使用这些非凡的动物。我们相信可以访问和促进对这种迷人自然实验的研究为发现的真正新颖可能性对人类再生医学的深远影响。