Larry Benowitz, PhD

Optic Nerve Regeneration

The optic nerve conveys visual information from the eye to the brain. If the optic nerve is injured or degenerates, the axons that arise from retinal ganglion cells (RGCs) are unable to grow back again and the parent cell bodies begin to die. This failure has devastating consequences for victims of traumatic optic nerve damage or of degenerative diseases such as glaucoma. We discovered that treatments that stimulate an inflammatory reaction in the eye cause RGCs to switch into an active growth state and begin regenerating their axons through the injured optic nerve. Using a cell culture model, we discovered that this regeneration requires a combination of three factors: a low molecular weight factor that is normally abundant in the eye, which we identified as mannose; elevation of intracellular cAMP; and a protein that is secreted by macrophages, which we identified as oncomodulin (Ocm). Dr. Yuqin Yin has shown that Ocm is secreted by inflammatory cells that enter the eye and accumulates in the retina, binding to a cell-surface receptor on RGCs. In the presence of appropriate co-factors, Ocm stimulates extensive regeneration in cell culture and in vivo. Reciprocally, agents that prevent Ocm from binding to its receptor strongly suppress inflammation-induced regeneration. These results establish Ocm as an important physiological signal between the immune response and neurons and as the principal mediator of inflammation-induced regeneration in vivo.

There are numerous signals in neurons' extracellular environment that suppress axon regeneration, but counteracting these signals is not sufficient to induce extensive optic nerve regeneration. However, when we counteract extracellular inhibitory signals and simultaneously activate RGCs' intrinsic growth program (via intraocular inflammation), we can obtain unprecedented levels of optic nerve regeneration. Studies by Dr. Kurimoto and other members of the lab show that optic nerve regeneration can also be amplified by combining intraocular inflammation with methods that de-repress particular intracellular signaling pathways. The long-term goal of this research is to identify molecular manipulations that enable RGCs to regenerate axons all the way to the appropriate centers in the brain and restore some level of vision.