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

• 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
• 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

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 唯一已知的哺乳动物物种，保留了显着的能力，增加再生愈合 在多个系统中发挥潜力。作为哺乳动物， Acomys是独特的，但不太可能远离人类治疗所需的那些。虽然Acomys 可能是开启我们自身再生能力的最佳钥匙， 在哺乳动物中，稳态修复与病理性纤维化相比，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监管，因此目前在生物医学研究中的使用有限。 我们的创新方法，使跨多个系统的快速研究一直是第一序列， 组装并注释了高质量的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，以更快地促进其在生物医学研究中的利用。我们 一个研究小组有大量的证据表明，来自不同成年Acomys组织的细胞 在原代培养物中生长得非常好。事实上，分离的Acomys成纤维细胞积极抵抗苦参碱介导的 通过改变基因表达和差异调节信号转导诱导成肌纤维细胞 体内平衡和再生途径的动力学。我们建议开发Acomys细胞系， 成人组织，用一系列荧光生物传感器工具对其进行遗传编码， 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。我们认为， 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。