This project seeks ways to enhance aqueous humor outflow for glaucoma therapy. Specifically it will (1) determine the outflow enhancing potential of agents by examining their effects on cytoskeletal, cell junctional and extracellular matrix interaction profiles in vitro and effects on outflow facility in vitro and vivo, (2) determine the in vivo morphological and physiological effects on outflow of long-term therapy with cytoskeleton modulating agents (H-7 or latrunculin B) used in combination with common glaucoma therapies or resulting from over-expression of viral vector delivered transgenes encoding for cytoskeleton modulating proteins (caldesmon and C3), (3) create a new primate model of glaucoma by excess exposure to cochlin or TGFb2 which will be more relevant for studies of glaucoma targeting aqueous outflow enhancement, (4) determine the mechanisms of intraocular pressure (IOP) reduction of other classes of potential glaucoma therapeutic agents (cannabinoids, nitric oxide donors, prostaglandin EP4 agonists, angiotensin and chymase), and their interactions with existing glaucoma therapies. In vitro cell studies will be conducted in human trabecular meshwork and ciliary muscle cells using immunohistochemistry. Aqueous outflow will be determined by measuring outflow facility and uveoscleral outflow in monkeys. Trabecular outflow facility will be measured in monkey anterior segments in organ culture. Intraocular pressure (Goldmann applanation tonometry) and aqueous humor formation (fluorophotometry) will be measured in monkeys. Lentiviral vectors will deliver genes to the outflow pathways following intracameral injection. Glaucoma model progression will be monitored by IOP, nerve fiber layer thickness and contour, and retinal and central function by electrophysiology. Structural parameters in the anterior segment of intact eyes and organ cultured anterior segments will be evaluated by light/electron microscopy, immunohistochemistry and quantitative morphometry. This project should increase our knowledge of the physiological, pharmacological, neural and morphological mechanisms and responses governing aqueous humor drainage, and provide insights into the therapeutic and toxicological mechanisms of current and putative antiglaucoma drugs. Such knowledge will contribute to the development of new antiglaucoma drugs and perhaps to understanding the underlying biochemical, physiological, and morphological basis of the human open angle glaucomas. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY002698-30
Application #
7490456
Study Section
Special Emphasis Panel (ZRG1-BDCN-H (93))
Program Officer
Agarwal, Neeraj
Project Start
1979-07-01
Project End
2010-08-31
Budget Start
2008-09-01
Budget End
2010-08-31
Support Year
30
Fiscal Year
2008
Total Cost
$190,316
Indirect Cost
Name
University of Wisconsin Madison
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Lee, Eun Suk; Rasmussen, Carol A; Filla, Mark S et al. (2014) Prospects for lentiviral vector mediated prostaglandin F synthase gene delivery in monkey eyes in vivo. Curr Eye Res 39:859-70
Aktas, Zeynep; Tian, Baohe; McDonald, Jared et al. (2014) Application of canaloplasty in glaucoma gene therapy: where are we? J Ocul Pharmacol Ther 30:277-82
Tian, Baohe; Kaufman, Paul L (2013) A Potential Application of Canaloplasty in Glaucoma Gene Therapy. Transl Vis Sci Technol 2:
Gabelt, B'ann T; Rasmussen, Carol A; Tektas, Ozan Y et al. (2012) Structure/function studies and the effects of memantine in monkeys with experimental glaucoma. Invest Ophthalmol Vis Sci 53:2368-76
Tian, Baohe; Kaufman, Paul L (2012) Comparisons of actin filament disruptors and Rho kinase inhibitors as potential antiglaucoma medications. Expert Rev Ophthalmol 7:177-187
Kiland, Julie A; Gabelt, B'ann T; Kaufman, Paul L (2011) Relationship of aqueous outflow resistance to age and total volume perfused in rhesus and cynomolgus monkeys. Invest Ophthalmol Vis Sci 52:6820-4
Elsmo, Elizabeth J; Kiland, Julie A; Kaufman, Paul L et al. (2011) Evaluation of rebound tonometry in non-human primates. Exp Eye Res 92:268-73
Gabelt, B'Ann T; Kaufman, Paul L; Rasmussen, Carol A (2011) Effect of nitric oxide compounds on monkey ciliary muscle in vitro. Exp Eye Res 93:321-7
Ly, Tina; Gupta, Neeru; Weinreb, Robert N et al. (2011) Dendrite plasticity in the lateral geniculate nucleus in primate glaucoma. Vision Res 51:243-50

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