Our research tries to answer a central question: Can we prevent the blindness caused by glaucoma?
Glaucoma is the second leading cause of blindness worldwide, affecting more than 60 million people. Glaucoma leads to the degeneration of retinal ganglion cell axons and eventually the retinal ganglion cells themselves, resulting in irreversible blindness. Retinal ganglion cells are the neurons in the retina that communicate the visual signal from the eye to the brain. Even though there are several different kinds of glaucoma, they all share the degeneration of the retinal ganglion cell axons (known as optic neuropathy) and eventual blindness.
The leading treatment for glaucoma is lowering of intraocular pressure (IOP), which can be elevated in patients with the disease. High IOP is a risk factor for glaucoma, but some patients do not have high IOP. In addition, there are patients who have high IOP, but do not develop glaucoma. Nevertheless, many patients experience a delay in the progression of their vision loss with IOP lowering treatment. Patients who do not experience a delay in their glaucoma with IOP lowering drugs (usually delivered as eye drops) may elect to undergo surgery to improve the drainage of their aqueous humor and thus, lower IOP.
Glaucoma research will enable us to determine the mechanism of retinal ganglion cell degeneration in glaucoma so that we can intervene. Here is a link to a book chapter describing some of our thinking:
Manipulating Glia to Protect RGCs in Glaucoma
In our lab, we identify potential targets and design interventions that will protect the retinal ganglion cells from degeneration and death. Our work focuses on the three overlapping areas described below.
Glia
We explore ways to manipulate glia to offer greater neuroprotection for retinal ganglion cells during glaucoma. In the retina, astrocytes and Müller glia maintain the extracellular environment to facilitate neuronal signaling. These glia cells also provide the neurons with factors that enable their function during times of stress. Astrocytes wrap the ganglion cell axon fascicles in the retina, optic nerve head and unmyelinated, proximal optic nerve, placing them in a unique position to provide life-sustaining factors to the first elements that degenerate in glaucoma. Our goal is to augment specific glial roles at certain times during glaucoma in order to prevent ganglion cell degeneration.
Related papers
“Quantitative correlation of optic nerve pathology with ocular pressure and corneal thickness in the DBA/2 mouse model of glaucoma.” Investigative Ophthalmology and Visual Science, 47:986-996, 2006.
“Whole retinal microarray analysis of glaucoma in DBA/2 mice.” Investigative Ophthalmology and Visual Science, 47:977-985, 2006.
“Reactive non-proliferative gliosis predominates in a chronic mouse model of glaucoma.” Glia 55(9):942-953, 2007.
“Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma,” Journal of Neuroscience 28(11):2735-2744, 2008.
“Minocycline reduces microglial activation and improves optic neuropathy in the DBA/2J mouse model of glaucoma,” Investigative Ophthalmology and Visual Science, 49(4):1437-1446, 2008.
“Early Reduction of Microglia Activation by Irradiation in a Model of Chronic Glaucoma.” PLoS ONE 7(8): e43602, 2012. doi:10.1371/journal.pone.0043602
Gangliosides
We endeavor to determine the contribution of gangliosides to glaucoma pathogenesis. The ganglioside GM1 undergoes changes in quantity and distribution during glaucoma. GM1 can alter cellular responses to growth factors and immunomodulators, making any observed changes potentially relevant for survival and function of retinal ganglion cells. Once we find how these changes occur, we can determine the impact on retinal ganglion cells and find ways to prevent any negative consequences to ganglion cell function and survival.
Related papers
“Heterogeneous Ganglioside Standards in LC-MS/MS: Sensitive Method for Quantifying the Major Molecular Components in Mono-Sialo Ganglioside Standards." J Anal Bioanal Tech S13:009, 2015.
Mitochondria
We work to establish whether mitochondrial dysfunction contributes to glaucoma development. Mitochondria provide energy to all cells; we have observed ways in which energy management in the optic nerve is not normal in our glaucoma model. We are following up this observation by analyzing mitochondrial function in the retina and optic nerve compartments. If we confirm mitochondrial dysfunction, we will develop ways to target the specific obstacle in ways that would preserve ganglion cell axon function.
Related papers
“Drp1 levels constitutively regulate mitochondrial dynamics and cell survival in cortical neurons.” Experimental Neurology 218(2): 274-285, 2009.
“Metabolic vulnerability disposes retinal ganglion cell axons to dysfunction in a model of glaucomatous degeneration.” Journal of Neuroscience 30(16):5644-52, 2010.
“Mitochondrial Morphology Differences and Mitophagy Deficit in Murine Glaucomatous Optic Nerve." Investigative Ophthalmology and Visual Science 56:1437–1446, 2015.
“Decreased Energy Capacity and Increased Autophagic Activity in Optic Nerve Axons with Defective Anterograde Transport." Investigative Ophthalmology and Visual Science, 56(13):8215-27, 2015.