Glaucoma is a leading cause of irreversible blindness and visual disability that has a major impact on the quality of life and productivity of millions of Americans. With no new pharmaceutical classes for treating glaucoma introduced into clinical practice since the 1990s, there remains a continuing need for improved regimes that treat glaucoma more effectively. Our long-term goal is to contribute to the development of these improved therapies by utilizing synergistic genetic approaches with mice and humans. Here, we focus on a sub-type of glaucoma, pigmentary glaucoma, and its major risk factor, pigment dispersion syndrome. Pigment dispersion is an alarmingly common condition characterized by aberrant release and collection of pigment throughout the anterior chamber of the eye. In most people, pigment dispersion causes no significant problems. However, in others, pigment dispersion leads to elevated intraocular pressure and pigmentary glaucoma. The factors initiating pigment dispersion and determining these very different potential outcomes are largely unknown. Our central hypothesis is that dispersed pigment elicits active, modifiable, physiological responses by the trabecular meshwork that are shaped by genetics and that dictate whether or not the insult progresses to secondary glaucoma. Using human genetics, we are studying families affected by pigment dispersion to identify genetic factors causing initiation of pigment dispersion. Using approaches with mice, we have developed an inducible mouse model for studying physiological responses to pigment dispersion and identified genetic suppressors of pigmentary glaucoma for studying potential treatments. Our objective in this proposal is to utilize and build on these resources to study molecular events contributing to pigment dispersion and its conversion to pigmentary glaucoma. To accomplish this, we propose: (SA1) to identify genes linked with pigmentary glaucoma using human genetics, (SA2) to define predictors of ocular responses to pigment dispersion using inducible mouse models, and (SA3) to identify suppressors of pigmentary glaucoma using mouse models.

Public Health Relevance

Glaucoma is a leading cause of irreversible blindness. Our research focuses on studies of pigmentary glaucoma, a common sub-type of glaucoma. The results will provide insight into the molecular pathways that lead to disease and may offer a pathway toward deployment of new glaucoma therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY017673-06A1
Application #
8630603
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Chin, Hemin R
Project Start
2006-07-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
6
Fiscal Year
2014
Total Cost
$300,878
Indirect Cost
$100,878
Name
University of Iowa
Department
Physiology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Gorniak, Thomas; Haraszti, Tamas; Garamus, Vasyl M et al. (2014) Nano-scale morphology of melanosomes revealed by small-angle X-ray scattering. PLoS One 9:e90884
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Trantow, Colleen M; Cuffy, Tryphena L; Fingert, John H et al. (2011) Microarray analysis of iris gene expression in mice with mutations influencing pigmentation. Invest Ophthalmol Vis Sci 52:237-48
Haraszti, Tamas; Trantow, Colleen M; Hedberg-Buenz, Adam et al. (2011) Spectral analysis by XANES reveals that GPNMB influences the chemical composition of intact melanosomes. Pigment Cell Melanoma Res 24:187-96

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