Fingert wins Glaucoma Research Foundation Grant
Friday, February 08, 2013
The Glaucoma Research Foundation has awarded Dr. Fingert a $40,000 Shaffer Grant for his application entitled "Molecular genetic study of normal tension glaucoma using transgenic mice". He and his collaborators at the University of Iowa (Drs. Arlene Drack and Wallace LM Alward) will use these funds to investigate the mechanisms by which defects in the TBK1 gene lead to optic nerve disease and glaucoma with transgenic mice." The abstract describing this research is listed below.
Vision loss and blindness due to glaucoma is a significant public health problem. However, many of the specific steps in the biological pathway that lead to central features of glaucoma (optic nerve damage and resulting visual field loss) are not well known, and this has hindered efforts for early detection and treatment of this condition. Consequently, there is a critical need to clarify the mechanism of disease for glaucoma at the molecular level. We recently identified a new glaucoma gene, TANK binding kinase 1 (TBK1). We discovered that copy number variations (duplications) of TBK1 are associated with cases of normal tension glaucoma (NTG) that occur in African American, Caucasian, and Asian patients. This discovery has helped to define autophagy as a central process in NTG pathogenesis.
Autophagy is a cellular process that recycles damaged organelles and proteins that, when out of balance, can lead to cell death. Prior studies have shown that autophagy is involved in retinal ganglion cell death. Our discovery that TBK1 is an NTG gene provides additional evidence that autophagy has an important role in the pathogenesis of NTG. TBK1 and two other genes that are associated with NTG, optineurin and Toll-like receptor 4, encode proteins that have essential functions in autophagy. These data further suggest that autophagy is a key process in the pathogenesis of glaucoma.
The goal of this proposal is to extend our discovery that duplication of TBK1 causes NTG by investigating the mechanism by which defects in this gene and autophagy regulation may lead to glaucoma using transgenic mice.
We have shown that TBK1 is specifically expressed in human retinal ganglion cells.
- We have shown that duplication of TBK1 in NTG patients leads to increase TBK1transcription. Our data suggest that overexpression of TBK1 leads to retinal ganglion cell death in NTG.
- We have reagents to produce transgenic mice in which TBK1 is overexpressed in retinal ganglion cells to recapitulate TBK1-associated human NTG. We have AAV2 virus in hand (with beta actin promoter and the human TBK1 cDNA) prepared by Dr. Hauswirth.
- We have extensive experience using viral vectors to generate mouse models of human ocular disease.
Specific Aim 1. Generate and characterize a transgenic mouse model of NTG with intravitreal injection of AAV2-TBK1. After injections, we will assess mice for signs of glaucomatous optic neuropathy with non-invasive methods (OCT imaging and photography) and histological methods (retinal ganglion cell counts, optic nerve axon counts, retinal nerve fiber thickness assessment, TUNEL assays, and immunolabeling of molecular makers of autophagy).
Significance. We will elucidate the mechanism of disease in one form of NTG. These studies may provide new insights into the basic biology of pressure-independent forms of glaucoma which may lead to novel therapies for NTG patients.