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.
Neuronal dysfunction is associated with impaired bone formation in broad conditions of osteogenesis. However, the mechanisms of nerve-bone crosstalk underlying these deficits remain largely unidentified. In this project, we will exploit te experimental flexibility of zebrafish (a model organism with limited use in bone and mineral research) to identify novel neural components mediating osteogenesis. In doing so, we will establish a novel in vivo screening strategy for osteoactive compound identification, an advancement with direct implications for bone therapeutic discovery.
