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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.

项目总结我们的目标是开发Acomys cahirinus作为一种新的替代哺乳动物模型系统，因为它们代表了唯一一种已知的哺乳动物物种，仍具有显著的再生愈合能力成年后跨越多个系统的潜力。作为哺乳动物，再生修复的分子途径 Acomys是独一无二的，但不太可能远离人类治疗所需的那些。尽管Acomys 可能是解锁我们自身再生能力和理清在哺乳动物中，动态平衡修复与病理性纤维化相比，Acomys动物的研究目的更多比其他啮齿动物模型受到严格的监管，因此目前在生物医学研究中的应用有限。我们能够跨多个系统进行快速研究的创新方法是先排序，汇编和注释一个高质量的马蹄莲基因组资源。我们的第二步是发展 Acomys细胞和转基因资源，以更快地促进其在生物医学研究中的应用。我们的多学科的Acomys研究小组有广泛的证据表明，来自不同成体Acomys组织的细胞在初级培养中生长得出奇地好。事实上，分离的Acomys成纤维细胞积极抵抗细胞因子介导的基因表达改变和信号转导差异调控对肌成纤维细胞的诱导动态平衡和再生途径的动力学。我们建议将Acomys细胞系从多个成人组织，用一系列报告KEY活性的荧光生物传感器工具对它们进行基因编码信号通路，产生必要的工具来解开Acomys的重要机制细节再生生物学。我们还致力于开发转基因Acomys技术和动物，以迅速促进更广泛的科学界对这些非凡动物的利用。我们相信，启用访问和促进对这一迷人的自然实验的研究为发现提供了真正新颖的可能性对人类再生医学的深远影响。