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Dev

Overview

Our current research is primarily focused on restoring vision after injury to the optic nerve. Although the mature optic nerve norm ally cannot regenerate when injured, we discovered that inducing a limited inflammatory reaction in the eye enables retinal ganglion cells (RGCs), the neurons that convey visual information from the eye to the brain, to regenerate axons well beyond the injury site. We identified the small Ca 2+ - binding protein on comodulin (Ocm) as a primary mediator of this phenomenon , and recently showed that SDF1 (from macrophages) complements the effects of Ocm. Combining intraocular inflammation with a cAMP analog and pten gene deletion enables some RGCs to regenerate axons from the eye to appropriate target areas in the brain. In other work, together with Drs. Paul Rosenberg and Yiqing Li, we found that injury to the optic nerve gives rise to changes in mul tiple retina l cell types that include elevation of glutamate from bipolar cells, nitric oxide from amacrine cells, and accumulation of free/mobile zinc (Zn 2+ ) in amacrine cells that is then exocytosed to influence RGCs . C helating Zn 2+ increases the ability of RGCs to survive and regenerate axons after optic nerve injury and has strongly synergistic effects with other treatments, boosting long - term survival of RGCs and lengthy axon regeneration . Most recently, we have identified a highly atypical, high - affinity receptor for Ocm that is essential for Ocm’s binding and biological activity; found that Ocm and its receptor also play a role discovered that another chemokine expressed in inflammatory cells, CCL5, is a potent stimulator of RGC survival and axon regenerati on which mediates most of the effects ascribed to a commonly used pro - regenerative treatment, CNTF gene therapy; discovered several of the key transcription factors that act as “master switches” for axon regene ration in RGCs; showed that the complement cascade and innate immune system participate in removing myelin debris from the site of optic nerve injury to facilitate regeneration; and that different growth factors have differential effects on the response pr operties of diverse subtypes of RGCs, enabling some to respond to Pten deletion , others to stop responding , and when combined, enable many subtypes to respond and extend lengthy axons. In the recent past, we have also studied the role of microglial activat ion and TNF -  in glaucoma ; and the role of inosine and the protein kinase Mst3b in regulating axon growth and functional recovery after stroke and spinal cord injury. Current research is focused on epigenetic regulation of axon regeneration ; inter - cellular signaling networks activated in the retina after optic nerve damage; remyelination of regenerating axons; clinically relevant approaches to optic nerve regeneration. Our research utilizes molecular biology, biochemistry, cell culture, histology, and anima l surgery and behavior.

The Benowitz Lab has had a long-standing interest in repairing the injured central nervous system (CNS) and, in particular, regeneration of the injured optic nerve. Most CNS neurons cannot regrow long-distance connections once they are damaged, and consequently, victims of stroke, spinal cord or optic nerve injury, traumatic brain injury, and various neurodegenerative diseases often sustain irreversible, devastating losses. The optic nerve, which conveys visual information from the retinal ganglion cells (RGCs) in the eye back to the brain, has been widely studied for insights that may help enhance regeneration throughout the CNS and for its relevance to diseases such as glaucoma, neurofibromatosis, and dominant optic atrophy. One surprising discovery has been that inducing an inflammatory reaction in the eye improves RGC survival after optic nerve injury and enables some of these cells to regenerate axons through the injured optic nerve. When combined with other treatments (deleting the Pten gene in RGCs and elevating levels of cAMP), intraocular inflammation enables some RGCs to regenerate axons from the eye all the way back to the brain and restore simple visual responses. We identified the primary mediators of inflammation-induced regeneration as oncomodulin (Ocm) and SDF1, and have identified a highly atypical cell-surface receptor to which Ocm binds to initiate regeneration. SDF1 and Ocm differentially affect the ability of various RGC subtypes to , respond to Pten deletion and regenerate axons. In other work, we identified key transcription factors that regulate the program of gene expression underlying axon regeneration, and identified the chemokine CCL5 as another potent growth factor for RGCs that mediates most effects associated with gene therapy for the growth factor CNTF. We also discovered that optic nerve injury affects multiple retinal cell types, leading to elevation of extracellular glutamate, nitric oxide, and ionic zinc. Some of these changes enable RGCs to respond to pro-regenerative treatments while others suppress RGC survival and axon regeneration. Other studies have demonstrated a prominent role of TNF-alpha in animal models of glaucoma; investigated the role of inosine in rewiring neural connections after stroke and spinal cord injury, and identified the molecular mechanisms underlying these effects.

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