Identifying mechanisms of coordinated outgrowth during zebrafish fin regeneration

项目摘要 该项目将为维克托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准备。申请人将遵循 多方面的研究和培训计划在俄勒冈州大学的监督下，主要赞助商博士。 Stankunas与共同赞助人John Postlethwait博士的额外指导。的根本目标 发育生物学是确定细胞和分子机制同步细胞行为， 复杂器官再生的谱系。斑马鱼的鳍完美地再现了它们的原始形态， 切除，使他们成为一个引人注目的例子和听话的研究模型的附件再生。一个 损伤诱导的去分化但有组织的称为芽基的细胞团产生替代鳍细胞 并指导再生生长。鳍的生长依赖于空间分离的增殖， 分化活动，逐步恢复组织化组织，包括与残端整合的射线骨 组织.主要的信号通路，信号产生和响应细胞，以及它们的一般作用（例如， 增长与分化）正在受到重视。然而，信号如何使时空 在细胞类型之间的协调行动在很大程度上仍然是神秘的。由新的单电池供电 转录组学，刘易斯博士将测试一个新的假设，调节间充质上皮样细胞状态 过渡形成了末端芽基的生长促进群体。他还将测试一个假设， 全身因素协调成骨细胞分化和生长。最后，刘易斯博士将绘制细胞类型 通过将复杂单细胞技术与 提供急性途径抑制的化学遗传学。总的来说，本提案将探讨和描述 在附肢再生过程中协调生长的创新模式和机制。总的来说，这些 见解将影响再生医学方法的设计，并提供一个框架，以了解 附件损伤修复。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）发展作为导师和教师的技能，以及4）参与 专业发展活动，以培养作为主要研究者取得成功的技能。UO，Institute of 分子生物学和UO的国际知名斑马鱼研究社区提供设施，设备， 与刘易斯博士的博士后研究和培训目标理想一致的知识环境。

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.