Identifying mechanisms of coordinated outgrowth during zebrafish fin regeneration

确定斑马鱼鳍再生过程中协调生长的机制

• 批准号: 10315962
• 负责人: Victor Maxwell Lewis
• 金额: $ 6.64万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315962
• 关键词: Acute; Biological Assay; Cell Nucleus; Cell Proliferation; Cells; Chromatin; Communication; Communities; Complex; Cues; Data Set; Defect; Development; Developmental Biology; Distal; Environment; Epidermis; Epithelial; Epithelial Attachment; Equipment; Excision; Fibroblast Growth Factor; Genes; Genetic; Genetic Transcription; Genomics; Glucocorticoids; Goals; Growth; Growth Factor; Human; Image; In Vitro; Injury; Institutes; Insulin; International; Intrinsic factor; Lead; Limb structure; Maps; Mentors; Mesenchymal; Mesenchyme; Modeling; Molecular; Molecular Biology; Natural regeneration; Oregon; Organ; Osteoblasts; Outcome; Pathway interactions; Phase; Population; Primary Cell Cultures; Principal Investigator; RNA; Receptor Signaling; Regenerative Medicine; Research; Research Training; Role; Signal Pathway; Signal Transduction; Source; Supervision; Swimming; Testing; Therapeutic; Time; Tissues; Training; Transposase; Universities; WNT Signaling Pathway; Work; Writing; Zebrafish; appendage; blastema; bone; career; cell behavior; cell type; chemical genetics; design; developmental genetics; empowered; healing; improved; in vivo; in vivo evaluation; injury and repair; innovation; insight; novel; organ injury; organ regeneration; osteoblast differentiation; regenerative; repaired; response; restoration; seal; single cell sequencing; single cell technology; single-cell RNA sequencing; skills; spatiotemporal; teacher; transcriptomics; wound epidermis

PROJECT SUMMARY This project will provide Dr. Victor Lewis with postdoctoral research training in vertebrate developmental genetics and genomics to prepare for a career as an academic principal investigator. The applicant will follow a multi-faceted research and training plan at the University of Oregon under supervision of lead sponsor Dr. Kryn Stankunas with additional mentoring from co-sponsor Dr. John Postlethwait. A fundamental goal of developmental biology is to identify the cellular and molecular mechanisms synchronizing cell behaviors across lineages for complex organ regeneration. Zebrafish fins perfectly recapitulate their original form following resection, making them a striking example of and tractable research model for appendage regeneration. An injury-induced de-differentiated but organized mass of cells called the blastema produces replacement fin cells and directs regenerative outgrowth. Fin outgrowth then depends on spatially segregated proliferation and differentiation activities that progressively restore organized tissue, including ray bones integrated with stump tissue. The major signaling pathways, the signal-producing and responding cells, and their general roles (e.g. growth vs. differentiation) are becoming appreciated. However, how signals enable spatiotemporally coordinated actions across cell types remains largely mysterious. Empowered by new single cell transcriptomics, Dr. Lewis will test a novel hypothesis that a regulated mesenchymal to epithelial-like cell state transition forms the outgrowth-promoting population of the distal blastema. He will also test a hypothesis how systemic factors coordinate osteoblast differentiation with fin outgrowth. Finally, Dr. Lewis will map the cell-type specific regulatory landscape of fin regeneration by integrating sophisticated single cell technologies with chemical genetics providing acute pathway inhibition. Collectively, this proposal will explore and characterize innovative models and mechanisms for coordinated outgrowth during appendage regeneration. Broadly, these insights will impact design of regenerative medicine approaches and provide a framework to understand appendage injury repair. Dr. Lewis’s training plan will broaden single-cell sequencing and technical research skills, 2) improve writing and communication skills, 3) develop skills as a mentor and teacher, and 4) engage in professional development activities to build skills to succeed as a principal investigator. The UO, Institute of Molecular Biology, and UO’s internationally known zebrafish research community provide facilities, equipment, and intellectual environment ideally aligned with Dr Lewis’s postdoctoral research and training goals.

项目摘要 该项目将为Victor Lewis博士提供脊椎动物发育的博士后研究培训 遗传学和基因组学为学术首席研究员的职业做准备。申请人将遵循 在首席赞助商Kryn博士的监督下，俄勒冈大学的多方面研究与培训计划 Stankunas，由John Postlethwait博士共同发起了额外的心理。一个基本目标 发育生物学是确定细胞和分子机制同步的细胞行为 复杂器官再生的谱系。斑马鱼鳍完美地概括了其原始形式 切除，使其成为附属物再生的罢工典范和可处理的研究模型。一个 损伤引起的去分化但有组织的细胞质量称为Blastema会产生替代鳍细胞 并指导再生生长。然后，生长的生长取决于空间隔离的增殖和 分化活动逐渐恢复有组织的组织，包括与树桩整合的射线骨头 组织。主要的信号通路，信号产生和响应细胞及其一般作用（例如 增长与差异化）得到了赞赏。但是，信号如何暂时启用空间 跨细胞类型的协调作用在很大程度上仍然是神秘的。由新单元授权 转录组学，刘易斯博士将检验一个新的假设，即调节的间质对上皮样细胞状态 过渡形成了远端胚芽的促进人群。他还将检验一个假设 全身因子将成骨细胞的分化与鳍片的生长协调。最后，刘易斯博士将映射细胞类型 通过将复杂的单细胞技术整合到Fin再生的特定调节景观 化学遗传学可提供急性途径抑制。总的来说，该建议将探索和表征 附属物再生过程中协调生长的创新模型和机制。从广义上讲，这些 见解将影响再生医学方法的设计，并提供一个框架来了解 附属损伤修复。刘易斯博士的培训计划将扩大单细胞测序和技术研究 技能，2）提高写作和沟通技巧，3）发展作为心理和老师的技能，4）参与 专业发展活动以建立技能，成为首席研究员的成功。 UO，研究所 分子生物学和UO国际知名的斑马鱼研究社区提供设施，设备， 智能环境理想地与刘易斯博士的博士后研究和培训目标保持一致。