Neuroskeletal Systems Biology in Zebrafish

 描述（由申请人提供）：使用简单的脊椎动物模型来鉴定骨的神经肌肉调节的分子和细胞基础代表了揭示高等生物体中同源途径的强大但未探索的策略。在这种情况下，体内筛选和快速基因敲除策略具有独特的潜力，以确定调节成骨的外骨骼通路，然而，这种策略在传统的骨修复体内模型中很大程度上是不可接近的。为了克服这一障碍，在本项目中，我们将开发再生斑马鱼尾鳍，这是一种膜内骨化模型，重现了哺乳动物骨形成的主要阶段，作为神经骨骼通路发现的快速遗传平台。特别是，我们的中心目标是整合定量骨成像在再生鳍与斑马鱼敲除和筛选策略，以确定新的神经调节骨生长，图案化和矿化。如果成功的话，这些研究将建立强大的体内检测方法，用于再生鳍中的神经骨骼通路评估，开发用于测量骨生长和矿化的技术工具箱，并确定神经骨骼发现的有价值的化学切入点。在这样做的过程中，该项目将推动再生斑马鱼鳍作为一种新的体内 为神经骨骼系统生物学的新兴领域的模型，并催化更广泛的途径和斑马鱼骨骼的治疗筛选工作。这项研究将在一个高度合作的咨询委员会（其集体成就包括再生生物学，斑马鱼骨骼发育，神经骨骼生物学和进化基因组学的开创性发现）的指导下进行，提供丰富的多学科研究经验。通过提供PI技术培训，专家指导和职业导师，因为他过渡到一个新的研究领域，这个项目将直接促进他的研究独立的进展。

 DESCRIPTION (provided by applicant): The use of simple vertebrate models to identify the molecular and cellular basis of neuromuscular regulation of bone represents a powerful yet unexplored strategy to uncover homologous pathways in higher organisms. In this context, in vivo screens and rapid gene knockdown strategies hold unique potential to identify extraskeletal pathways regulating osteogenesis, however such strategies are largely inaccessible in traditional in vivo models of bone anabolism. Toward overcoming this hurdle, in this project we will develop the regenerating zebrafish tail fin, a model of intramembranous ossification that recapitulates the major phases of mammalian bone formation, as a rapid genetic platform for neuroskeletal pathway discovery. In particular, our central objective is to integrate quantitative bone imaging in the regenerating fin with zebrafish knockdown and screening strategies to identify novel neural regulators of bone outgrowth, patterning, and mineralization. If successful, these studies will establish powerful in vivo assays for neuroskeletal pathway assessment in the regenerating fin, develop the technological toolbox for measuring bone growth and mineralization in this process, and identify valuable chemical entry points for neuroskeletal discovery. In doing so, this project will advance the regenerating zebrafish fin as a novel in vivo model for the emerging field of neuroskeletal systems biology, and catalyze broader pathway and therapeutic screening efforts in the zebrafish skeleton. This research will be carried out under the mentorship of a highly collaborative advisory committee (whose collective achievements include seminal findings in regenerative biology, zebrafish skeletal development, neuroskeletal biology, and evolutionary genomics), providing a rich, multidisciplinary research experience. By providing the PI technical training, expert guidance, and career mentorship as he transitions to a new research field, this project will directly facilitate his progression to research independence.