This grant has focused in the past on determining the potential role of factors induced by mechanical stress in trabecular meshwork (TM) cells as modulators of Schlemm's canal (SC) endothelium permeability and overall outflow facility. A major accomplishment towards this purpose was the success in growing SC cells in culture. Our studies have documented the activation of the transforming growth factor beta 1 (TGF-beta1) and interleukin 6 (IL-6) promoters, as well as the increased production of these cytokines in TM cells in response to mechanical stress both in human TM (HTM) cells in culture and perfused porcine anterior segments. We have also shown that a subpopulation of HTM cells is characterized by high levels of expression of the gene encoding for chitinase 3-like 1 (CHI3L1), a protein known to inhibit the production of proinflammatory cytokines. Both TGF-beta1&IL-6 are known to increase vascular endothelial permeability, and we have documented that perfusion of IL-6 increases outflow facility. We therefore hypothesize that both TGF-beta1 and IL-6 can act to increase the permeability of the endothelium of SC. An earlier study supported by this grant showed that certain kinds of mechanical stress could influence the mitogen-activated protein kinase (MARK) pathways. Since there are known relationships, direct and indirect, between IL-6, TGF-beta1, and CHI3L1 and the MARK pathway, we hypothesize that a molecular mechanism mediating these responses includes the involvement of an autocrine amplification loop between TGF-beta1 and MAPKs, which leads to increased expression of certain cytokines including IL-6;and that CHI3L1 expression acts to negatively modulate the stress-induced induction of TGF-beta1 and IL-6. We further hypothesize that unbalanced increased expression of CHI3L1 in the outflow pathway might result in an increase in outflow resistance with implication for glaucoma pathogenesis. To test our hypothesis, we propose the following 3 specific aims: SA1) determine whether activation of TGF-beta1and IL-6 in TM cells results in increased outflow facility in situ through effects on SC endothelium;SA2) evaluate whether the induction of IL-6 by mechanical stress in outflow pathway cells involves an amplifying loop between TGF-beta1 and MAPKs;and SA3) evaluate if the CHI3L1 acts to negatively modulate the stress-induced induction of TGF-beta1 and IL-6, thereby causing an increase in aqueous humor outflow resistance. Relevance: This project has the potential to increase our understanding of both normal and abnormal outflow pathway function and to lead to new treatments for glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY001894-33
Application #
7994777
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Agarwal, Neeraj
Project Start
1992-08-01
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2012-11-30
Support Year
33
Fiscal Year
2011
Total Cost
$470,824
Indirect Cost
Name
Duke University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Gonzalez, Pedro; Li, Guorng; Qiu, Jianming et al. (2014) Role of microRNAs in the trabecular meshwork. J Ocul Pharmacol Ther 30:128-37
Huang, Wei; Li, Guorong; Qiu, Jianming et al. (2013) Protective effects of resveratrol in experimental retinal detachment. PLoS One 8:e75735
Wu, Jing; Li, Guorong; Luna, Coralia et al. (2012) Endogenous production of extracellular adenosine by trabecular meshwork cells: potential role in outflow regulation. Invest Ophthalmol Vis Sci 53:7142-8
Luna, Coralia; Li, Guorong; Huang, Jianyong et al. (2012) Regulation of trabecular meshwork cell contraction and intraocular pressure by miR-200c. PLoS One 7:e51688
Kumar, Janardan; Epstein, David L (2011) Rho GTPase-mediated cytoskeletal organization in Schlemm's canal cells play a critical role in the regulation of aqueous humor outflow facility. J Cell Biochem 112:600-6
Luna, Coralia; Li, Guorong; Qiu, Jianming et al. (2011) Cross-talk between miR-29 and transforming growth factor-betas in trabecular meshwork cells. Invest Ophthalmol Vis Sci 52:3567-72
Luna, Coralia; Li, Guorong; Qiu, Jianming et al. (2011) MicroRNA-24 regulates the processing of latent TGFýý1 during cyclic mechanical stress in human trabecular meshwork cells through direct targeting of FURIN. J Cell Physiol 226:1407-14
Li, Guorong; Luna, Coralia; Qiu, Jianming et al. (2011) Role of miR-204 in the regulation of apoptosis, endoplasmic reticulum stress response, and inflammation in human trabecular meshwork cells. Invest Ophthalmol Vis Sci 52:2999-3007
Li, Guorong; Luna, Coralia; Navarro, Iris D et al. (2011) Resveratrol prevention of oxidative stress damage to lens epithelial cell cultures is mediated by forkhead box O activity. Invest Ophthalmol Vis Sci 52:4395-401
Li, Guorong; Luna, Coralia; Qiu, Jianming et al. (2010) Targeting of integrin beta1 and kinesin 2alpha by microRNA 183. J Biol Chem 285:5461-71

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