This project seeks to develop new treatments for glaucoma based on the response of ocular tissues to the effects of intraocular pressure (IOP) related stress. It studies how the sclera affects injury to retinal ganglion cells (RGC) by producing strain in the optic nerve head. Previously, the PI has quantitatively studied how IOP- related stress is translated into RGC axonal injury, using histological, biochemical and in vivo methods. Translating these findings to a new mouse model of induced glaucoma, which shares several features with the human disease, his initial studies have uniquely determined that mouse strains differ in glaucoma susceptibility. One susceptible strain has more compliant sclera in inflation tests, and the hypothesis is that this contributes to RGC death. To study key scleral elements that cause greater glaucoma damage and to alter these to produce new treatments, mouse strains with genetically altered sclera have been selected and bred that have properties that could make glaucoma damage more likely: e.g., long axial length, thin sclera, or altered scleral molecular composition. Glaucoma has been induced in pilot studies in these strains to detect differential glaucoma sensitivity. To determine which scleral features are contributory or protective, integrated structural and functional studies of mouse sclera are carried out through collaborations with mechanical engineer Thao Nguyen, biomedical engineer Justin Hanes, and Gulgun Tezel (University of Louisville) who is expert in proteomic analysis of ocular tissues. With Dr Nguyen, the PI developed inflation tests for human and mouse eyes that permit finite element models of scleral behavior in normal and glaucoma eyes. With the Hanes'lab, PI has produced a technique that describes intact scleral tissue diffusion, quantifying changes in scleral properties induced by experimental mouse glaucoma. Drs Quigley and Tezel have begun proteomic and detailed scleral biochemical studies of relevant molecules that showed alteration in induced glaucoma in the mouse. The integration of these complementary methods into cohesive glaucoma studies in normal mice and mice with targeted alterations in specific connective tissue molecules is the unified theme of the present application. By determining which molecules and functional effects are instrumental in potentiating glaucoma, new treatment approaches will be tested. Experiments will either weaken specific scleral elements or increase their molecular cross-linking as potential therapies. Specific pathways of connective tissue pathology related to TGF? activation will be inhibited in one of the genetically altered mouse models, a phenocopy of the human Marfan syndrome, to test the linkage between scleral composition, scleral response to chronic effects of IOP elevation, and RGC loss. The work is likely to produce new neuroprotective treatments for glaucoma as well as candidate genes relevant to glaucoma.

Public Health Relevance

Studies of normal and genetically altered mouse strains subjected to experimental glaucoma will identify scleral features that influence retinal ganglion cell loss. Chemical and pharmacological treatments are tested as novel neuroprotective approaches and new candidate genes may be identified.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY002120-33A1
Application #
8371545
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Chin, Hemin R
Project Start
1977-08-01
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
33
Fiscal Year
2012
Total Cost
$549,950
Indirect Cost
$199,950
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Fu, Jie; Sun, Fengying; Liu, Wenhua et al. (2016) Subconjunctival Delivery of Dorzolamide-Loaded Poly(ether-anhydride) Microparticles Produces Sustained Lowering of Intraocular Pressure in Rabbits. Mol Pharm 13:2987-95
Oglesby, Ericka N; Tezel, Gülgün; Cone-Kimball, Elizabeth et al. (2016) Scleral fibroblast response to experimental glaucoma in mice. Mol Vis 22:82-99
Quigley, Harry A; Pitha, Ian F; Welsbie, Derek S et al. (2015) Losartan Treatment Protects Retinal Ganglion Cells and Alters Scleral Remodeling in Experimental Glaucoma. PLoS One 10:e0141137
Pijanka, Jacek K; Spang, Martin T; Sorensen, Thomas et al. (2015) Depth-dependent changes in collagen organization in the human peripapillary sclera. PLoS One 10:e0118648
Coudrillier, Baptiste; Pijanka, Jacek; Jefferys, Joan et al. (2015) Collagen structure and mechanical properties of the human sclera: analysis for the effects of age. J Biomech Eng 137:041006
Coudrillier, Baptiste; Pijanka, Jacek K; Jefferys, Joan L et al. (2015) Glaucoma-related Changes in the Mechanical Properties and Collagen Micro-architecture of the Human Sclera. PLoS One 10:e0131396
Girard, Michaël J A; Dupps, William J; Baskaran, Mani et al. (2015) Translating ocular biomechanics into clinical practice: current state and future prospects. Curr Eye Res 40:1-18
Coudrillier, Baptiste; Pijanka, Jacek; Jefferys, Joan et al. (2015) Effects of age and diabetes on scleral stiffness. J Biomech Eng 137:
Murienne, Barbara J; Jefferys, Joan L; Quigley, Harry A et al. (2015) The effects of glycosaminoglycan degradation on the mechanical behavior of the posterior porcine sclera. Acta Biomater 12:195-206
Pijanka, Jacek K; Kimball, Elizabeth C; Pease, Mary E et al. (2014) Changes in scleral collagen organization in murine chronic experimental glaucoma. Invest Ophthalmol Vis Sci 55:6554-64

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