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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.

项目概要我们的目标是将 Acomys cahirinus 开发为新的替代哺乳动物模型系统，因为它们代表唯一已知的保留了增强再生愈合能力的哺乳动物物种成年后跨多个系统的潜力。作为哺乳动物，再生修复的分子途径 Acomys 是独一无二的，但与人类治疗所需的药物相去甚远。虽然阿科米斯可能是释放我们自身再生能力和理清两者之间关系的最佳钥匙哺乳动物的稳态修复与病理性纤维化，用于研究目的的 Acomys 动物更多与其他啮齿动物模型相比，其受到严格监管，因此目前在生物医学研究中的使用有限。我们实现跨多个系统快速研究的创新方法是首先进行排序，组装并注释高质量的 Acomys cahirinus 基因组资源。我们的第二步是开发 Acomys 细胞和转基因资源可更快速地促进其在生物医学研究中的利用。我们的多学科 Acomys 研究小组拥有大量证据表明来自不同成人 Acomys 组织的细胞在原代培养物中生长得惊人地好。事实上，分离的 Acomys 成纤维细胞主动抵抗细胞因子介导的通过改变基因表达和差异调节信号转导诱导肌成纤维细胞稳态和再生途径的动力学。我们建议从多种细胞中开发 Acomys 细胞系成人组织，用一系列荧光生物传感器工具对它们进行基因编码，这些工具报告关键的活性信号通路，生成必要的工具来揭示 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，以快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令人着迷的自然实验的研究提供了真正新颖的发现可能性对人类再生医学产生深远影响。