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)
Type
Research Project (R01)
Project #
5R01EY002120-35
Application #
8703698
Study Section
(DPVS)
Program Officer
Chin, Hemin R
Project Start
Project End
Budget Start
Budget End
Support Year
35
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kimball, Elizabeth C; Nguyen, Cathy; Steinhart, Matthew R et al. (2014) Experimental scleral cross-linking increases glaucoma damage in a mouse model. Exp Eye Res 128:129-40
Steinhart, Matthew R; Cone-Kimball, Elizabeth; Nguyen, Cathy et al. (2014) Susceptibility to glaucoma damage related to age and connective tissue mutations in mice. Exp Eye Res 119:54-60
Xu, Qingguo; Boylan, Nicholas J; Suk, Jung Soo et al. (2013) Nanoparticle diffusion in, and microrheology of, the bovine vitreous ex vivo. J Control Release 167:76-84
Quigley, Harry A; Cone, Frances E (2013) Development of diagnostic and treatment strategies for glaucoma through understanding and modification of scleral and lamina cribrosa connective tissue. Cell Tissue Res 353:231-44
Nguyen, Cathy; Cone, Frances E; Nguyen, Thao D et al. (2013) Studies of scleral biomechanical behavior related to susceptibility for retinal ganglion cell loss in experimental mouse glaucoma. Invest Ophthalmol Vis Sci 54:1767-80
Cone-Kimball, Elizabeth; Nguyen, Cathy; Oglesby, Ericka N et al. (2013) Scleral structural alterations associated with chronic experimental intraocular pressure elevation in mice. Mol Vis 19:2023-39
Soto, Ileana; Pease, Mary E; Son, Janice L et al. (2011) Retinal ganglion cell loss in a rat ocular hypertension model is sectorial and involves early optic nerve axon loss. Invest Ophthalmol Vis Sci 52:434-41
Myers, Kristin M; Cone, Frances E; Quigley, Harry A et al. (2010) The in vitro inflation response of mouse sclera. Exp Eye Res 91:866-75
Pease, Mary Ellen; Zack, Donald J; Berlinicke, Cynthia et al. (2009) Effect of CNTF on retinal ganglion cell survival in experimental glaucoma. Invest Ophthalmol Vis Sci 50:2194-200
Ueno, Shinji; Pease, Mary Ellen; Wersinger, Delphine M Bonnet et al. (2008) Prolonged blockade of VEGF family members does not cause identifiable damage to retinal neurons or vessels. J Cell Physiol 217:13-22

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