The long-term goal of this project is to understand the mechanisms for cannabinoids to lower intraocular pressure (IOP), and to provide a basis for developing novel cannabinoids with improved IOP-lowering properties, and devoid of psychoactive side-effects of marijuana. The central hypothesis to be tested in this proposal is that cannabinoids act on specific cannabinoid receptors in multiple targets of the outflow pathways to exert their IOP-lowering effects. To test this hypothesis, the following specific aims are planned. (1) To test the effects of cannabinoid ligands and the roles of cannabinoid receptors on outflow facility with perfused human ocular anterior segment, using recently developed high affinity and/or subtype-selective cannabinoid ligands. (2) To map the distribution of cannabinoid receptor subtypes in two potential targets of cannabinoids, trabecular meshwork and ciliary muscle. (3) To characterize ligand binding properties and signal transduction mechanisms of cannabinoid receptors in trabecular meshwork and ciliary muscle cells. (4) To determine the effects of cannabinoid ligands, the roles of cannabinoid receptors, and cannabinoid signaling pathways in regulating the cellular functions (such as cell cytoskeleton and matrix metalloproteases) of trabecular meshwork and ciliary muscle cells. A combination of molecular biology, cell biology and pharmacology approaches will be applied to the proposed research. Attempts will be made to correlate information gained from in vitro experiments with ex vivo organ perfusion studies in order to understand the roles of cannabinoid receptors and the mechanisms for the effects of cannabinoids on aqueous humor outflow. By investigating the mechanisms underlying the IOP-lowering effects of cannabinoids, this study may facilitate the discovery of more effective anti-glaucoma cannabinoid ligands. By deciphering specific ocular cannabinoid receptor subtypes that are involved in the IOP-lowering effects of cannabinoids, this study may help to separate the desired IOP-lowering effects of cannabinoids from their undesired psychoactive side-effects.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013632-03
Application #
6923583
Study Section
Special Emphasis Panel (ZRG1-VISA (02))
Program Officer
Liberman, Ellen S
Project Start
2003-08-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$294,000
Indirect Cost
Name
University of Louisville
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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Kumar, Pritesh; Song, Zhao-Hui (2014) CB2 cannabinoid receptor is a novel target for third-generation selective estrogen receptor modulators bazedoxifene and lasofoxifene. Biochem Biophys Res Commun 443:144-9
Kumar, Pritesh; Kumar, Akhilesh; Song, Zhao-Hui (2014) Structure-activity relationships of fatty acid amide ligands in activating and desensitizing G protein-coupled receptor 119. Eur J Pharmacol 723:465-72
Kumar, Pritesh; Song, Zhao-Hui (2013) Identification of raloxifene as a novel CB2 inverse agonist. Biochem Biophys Res Commun 435:76-81
Qiao, Zhuanhong; Kumar, Akhilesh; Kumar, Pritesh et al. (2012) Involvement of a non-CB1/CB2 cannabinoid receptor in the aqueous humor outflow-enhancing effects of abnormal-cannabidiol. Exp Eye Res 100:59-64
Kumar, Akhilesh; Qiao, Zhuanhong; Kumar, Pritesh et al. (2012) Effects of palmitoylethanolamide on aqueous humor outflow. Invest Ophthalmol Vis Sci 53:4416-25
He, Fang; Kumar, Akhilesh; Song, Zhao-Hui (2012) Heat shock protein 90 is an essential molecular chaperone for CB2 cannabinoid receptor-mediated signaling in trabecular meshwork cells. Mol Vis 18:2839-46
Carrasquer, Alex; Nebane, Nstang M; Williams, Walter M et al. (2010) Functional consequences of nonsynonymous single nucleotide polymorphisms in the CB2 cannabinoid receptor. Pharmacogenet Genomics 20:157-66
Nebane, Ntsang M; Hurst, Dow P; Carrasquer, Carl A et al. (2008) Residues accessible in the binding-site crevice of transmembrane helix 6 of the CB2 cannabinoid receptor. Biochemistry 47:13811-21

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