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: 10516719
• 负责人: Victor Maxwell Lewis
• 金额: $ 6.98万
• 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/10516719
• 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; rational design; 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.

项目概要 该项目将为维克多·刘易斯博士提供脊椎动物发育方面的博士后研究培训 遗传学和基因组学，为学术首席研究员的职业生涯做好准备。申请人将遵循 在主要发起人 Kryn 博士的监督下，俄勒冈大学的多方面研究和培训计划 斯坦库纳斯得到了共同发起人约翰·波斯尔思韦特博士的额外指导。一个基本目标是 发育生物学的目的是确定同步细胞行为的细胞和分子机制 复杂器官再生的谱系。斑马鱼的鳍完美再现了它们原来的形状 切除，使它们成为附肢再生的引人注目的例子和易于处理的研究模型。一个 损伤引起的去分化但有组织的细胞团（称为芽基）产生替代的鳍细胞 并指导再生生长。鳍的生长取决于空间隔离的增殖和 逐步恢复有组织组织的分化活动，包括与残肢整合的射线骨 组织。主要信号通路、信号产生和响应细胞及其一般作用（例如， 增长与差异化）越来越受到重视。然而，信号如何实现时空 跨细胞类型的协调作用在很大程度上仍然是个谜。全新单电池赋能 转录组学方面，刘易斯博士将测试一个新的假设，即受调节的间充质到上皮样细胞状态 转变形成远端胚基的促进生长群体。他还将检验一个假设 全身因素协调成骨细胞分化与鳍生长。最后，刘易斯博士将绘制细胞类型图 通过将复杂的单细胞技术与鳍再生的特定监管环境相结合 化学遗传学提供急性途径抑制。总的来说，该提案将探索并描述 附肢再生过程中协调生长的创新模型和机制。广义上讲，这些 见解将影响再生医学方法的设计，并提供一个框架来理解 附肢损伤修复。刘易斯博士的培训计划将拓宽单细胞测序和技术研究 技能，2) 提高写作和沟通技能，3) 培养作为导师和老师的技能，以及 4) 参与 专业发展活动，以培养作为首席研究员取得成功的技能。俄勒冈大学研究所 分子生物学和俄勒冈大学国际知名的斑马鱼研究社区提供设施、设备、 和智力环境与刘易斯博士的博士后研究和培训目标完美契合。