Retinal Ganglion Cell Neuroprotection in Animal Models of Glaucoma
Glaucoma is a consequence of an increased intra-ocular pressure which causes retinal ganglion cells (the cells connecting the retina to the brain and forming the optic nerve) to degenerate, leading to a loss of vision over time. The molecular mechanisms triggering neuronal death are unknown. Evidence in the literature showed that the inhibition of a specific type of receptor (the Eph-tyrosine kinase receptor A4 -EphA4) expressed on the membranes of neurons and glial cells enhances neuronal regeneration in spinal cord and optic nerve injury models, decreases axonal pathology in MS and is the only disease-modifier gene identified so far in ALS, suggesting that EphA4 is a detrimental factor for neuron survival/regeneration.
Is the connectivity rearranged in the superior colliculus during retinal cell degeneration? Does the visual system adapt to counterbalance the loss of retinal neurons? Could the inhibition of EphA4 signaling in retinal ganglion cells protect them from degeneration in animal models of glaucoma?
We will induce elevated intra-ocular pressure in an animal model devoid of EphA4 (EphA4KO mouse) and in animal model (wild-type mouse) treated with antagonistic peptides/small molecules interfering with EphA4 signaling. We will analyze retinal ganglion cell degeneration and visual network integrity in the superior colliculus using specific cellular/molecular markers and neural tracing coupled to brain imaging in these models. We will also check the relevance of the mechanosensors mentioned above (project 1) in the progression of glaucoma as these receptors might sense increased intra-ocular pressure and trigger neuronal degeneration.