It is now well established that a genetic component may contribute to glaucoma, and several glaucoma-associated genes have been identified. The first identified and the most studied gene is MYOCILIN, which is heavily expressed in and secreted by the trabecular meshwork, one of the key components in the aqueous humor outflow system of the eye. This gene is also expressed in non-ocular tissues. The functions of the encoded protein, myocilin, are still not fully understood. We demonstrated that expression of myocilin mutants may have a sensitization effect which can lead to a severe phenotype in combination with oxidative stress. Myocilin mutants may confer different sensitivities to oxidative stress depending upon the mutation. The synergystic effect of mutant myocilin and oxidative stress may lead to the loss of cells in the trabecular meshwork which is regarded as one of potential mechanisms for glaucoma pathogenesis. We showed that myocilin interacts with alpha-syntrophin, a cytoplasmic component of dystrophin-associated protein complex (DAPC). Myocilin was co-precipitated with other components of DAPC including dystrobrevin, dystrophin, and dystroglycan in mouse skeletal muscle. Our data suggest that myocilin may be involved in the recruitment of alpha-syntrophin to the complex, and it may contribute to the stabilization of DAPC. Furthermore, the skeletal muscles of transgenic mice expressing high levels of myocilin were enlarged compared to those observed for wild-type mice. We suggest that myocilin may regulate hypertrophy and atrophy signaling pathways through stabilization of DAPC in skeletal and ciliary muscles. In collaboration with Dr. T. Iwata (National Institute of Sensory Organs, Tokyo, Japan), we characterized transgenic mice expressing mutated optineurin. Mutations in this gene may lead to normal tension glaucoma in humans. We demonstrated that transgenic mice expressing the Glu50Lys mutation of optineurin developed a phenotype which mimics the clinical features of normal tension glaucoma patients including neuropathy of the optic disc and degeneration of the retinal ganglion cells at normal IOP. Besides studying the pathophysiology of glaucoma, we are also interested in potential treatments for the disease. Glaucoma is associated with impairment in retrograde transport of neurotrophic factors to retinal ganglion cell bodies. Mesenchymal stem cell (MSC) transplantation appears to be protective in a variety of neurodegenerative disorders of the brain and spinal cord, in part by neurotrophic factor secretion. Thus, we have been investigating a potential role of MSC transplantation as a therapy for glaucoma in collaboration with Dr. K. Martin (Cambridge University, Great Britain). MSCs were isolated from the bone marrow of adult wild type and transgenic rats that ubiquitously express green fluorescent protein. MSCs were transplanted intravitreally one week before, or intravenously on the day of, ocular hypertension induction by laser photocoagulation of the trabecular meshwork. Following intravitreal transplantation, MSCs survived for at least five weeks. Cells were found mainly in the vitreous cavity, though a small proportion of discrete cells migrated into the host retina. Following intravenous transplantation, MSCs did not migrate into the injured eye. Intravitreal MSC transplantation resulted in a significant increase in overall RGC survival (p<0.01) as well as a significant decrease in the rate of RGC loss normalized to cumulative intraocular pressure exposure (p<0.05). Intravenous transplantation had no effect on RGC survival. We concluded that local, but not systemic, transplantation of MSCs was protective in a rat model of laser-induced ocular hypertensive glaucoma. Autologous intravitreal transplantation of MSCs should be investigated further as a potential neuroprotective therapy for glaucoma patients.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAEY000318-13
Application #
8149149
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2010
Total Cost
$1,435,953
Indirect Cost
Name
U.S. National Eye Institute
Department
Type
DUNS #
City
State
Country
Zip Code
Mead, Ben; Tomarev, Stanislav (2018) Retinal ganglion cell neuroprotection by growth factors and exosomes: lessons from mesenchymal stem cells. Neural Regen Res 13:228-229
Mead, Ben; Amaral, Juan; Tomarev, Stanislav (2018) Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Promote Neuroprotection in Rodent Models of Glaucoma. Invest Ophthalmol Vis Sci 59:702-714
Joe, Myung Kuk; Lieberman, Raquel L; Nakaya, Naoki et al. (2017) Myocilin Regulates Metalloprotease 2 Activity Through Interaction With TIMP3. Invest Ophthalmol Vis Sci 58:5308-5318
Takahama, Shokichi; Adetunji, Modupe O; Zhao, Tantai et al. (2017) Retinal Astrocytes and GABAergic Wide-Field Amacrine Cells Express PDGFR?: Connection to Retinal Ganglion Cell Neuroprotection by PDGF-AA. Invest Ophthalmol Vis Sci 58:4703-4711
Mead, Ben; Tomarev, Stanislav (2017) Bone Marrow-Derived Mesenchymal Stem Cells-Derived Exosomes Promote Survival of Retinal Ganglion Cells Through miRNA-Dependent Mechanisms. Stem Cells Transl Med 6:1273-1285
Mead, Ben; Tomarev, Stanislav (2016) Evaluating retinal ganglion cell loss and dysfunction. Exp Eye Res 151:96-106
Morgan, Joshua T; Kwon, Heung Sun; Wood, Joshua A et al. (2015) Thermally labile components of aqueous humor potently induce osteogenic potential in adipose-derived mesenchymal stem cells. Exp Eye Res 135:127-33
Joe, Myung Kuk; Nakaya, Naoki; Abu-Asab, Mones et al. (2015) Mutated myocilin and heterozygous Sod2 deficiency act synergistically in a mouse model of open-angle glaucoma. Hum Mol Genet 24:3322-34
Johnson, Thomas V; DeKorver, Nicholas W; Levasseur, Victoria A et al. (2014) Identification of retinal ganglion cell neuroprotection conferred by platelet-derived growth factor through analysis of the mesenchymal stem cell secretome. Brain 137:503-19
Kwon, Heung Sun; Nakaya, Naoki; Abu-Asab, Mones et al. (2014) Myocilin is involved in NgR1/Lingo-1-mediated oligodendrocyte differentiation and myelination of the optic nerve. J Neurosci 34:5539-51

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