Feng-Quan Zhou, associate professor of orthopaedic surgery, and his basic science lab at The Johns Hopkins University are performing leading-edge neuronal morphogenesis research — specifically, how to promote axon regeneration after injury. Zhou’s current focus is optic nerve regeneration for treatment of glaucoma, but his research applies to several devastating diseases including osteoarthritis, Alzheimer’s and Parkinson’s disease, and paralysis caused by spinal cord injuries.
Zhou’s lab uses a two-pronged approach to study nerve regeneration. One involves examining the optimal environment for regrowth (the peripheral nervous system, which — unlike the central nervous system — can regenerate). The other involves manipulating intrinsic properties to stimulate growth (activating pro-regenerative pathways through epigenetic modification).
“At my lab, we are familiar with not only the peripheral nervous system, but also the central nervous system, and that is important,” says Zhou. “So we have the unique ability to compare the two systems and apply knowledge from the peripheral to the central nervous system.” To manipulate the intrinsic properties, Zhou studies ways to alter gene transcription to “switch on” the capacity to regrow, which means he must first identify changes in gene expression that occur after injury.
Using a machine that can perform single-cell RNA sequencing, Zhou can create a library of chain transcriptions for 10,000 neurons. “Now you can find out if some neurons regenerate better than others or if some cannot regenerate at all. Isolating functionality was not possible when you were only able to get a summary of sequencing of a lot of neurons together,” explains Zhou.
Using cultured cell models, Zhou can then change gene expression in the neuron and monitor the effects on regeneration. New technologies make the tissue transparent, enabling visualization of the axon, so the whole tissue can be imaged without any cutting. “You can reconstruct a 3D image of the axon regeneration inside the nerve,” says Zhou. “Not many other labs around the world can create an optic regeneration model, change gene expression and do imaging of the nerve.” Zhou’s collaborators at the Johns Hopkins Wilmer Eye Institute analyze the raw data Zhou’s experiments generated. Zhou believes this collaboration is key to translating his research because physicians typically understand patients’ experiences with glaucoma better than basic scientists do. “Maybe the physician can put the pieces of my data together,” he says.
In addition to stimulating optic nerve regeneration after injury, Zhou’s lab is also interested in identifying markers for early detection of glaucoma. In asymptomatic patients without increased intraocular pressure, glaucoma can go undetected, leading to irreversible vision loss. An early detection system could enable patients with glaucoma to retain their vision longer by delaying the disease’s progress.
The groundwork this research laid could be used as a model to treat spinal cord injuries — a future area of research for Zhou. “All the genes supporting optic nerve regeneration are very likely to support spinal cord regeneration,” says Zhou, suggesting hope that paralysis may someday be reversible.
Published in Orthopaedic Surgery Winter 2020.
