Our hypothesis is that cellular senescence in the aqueous humor outflow pathway is involved in the pathogenesis of the increase in outflow resistance that occurs in many types of glaucoma. More specifically, we hypothesize that the different kinds of chronic stress over time affecting the cells of the outflow pathway and, in particular, oxidative stress, lead to the progressive accumulation of misfolded proteins which overwhelm the degradative capacity of the proteasome in outflow pathway cells; that this results in chronic activation of the ER stress response which, in turn, activates the MKK3/MKK6/p38MAPK/TGFbeta pathway and triggers a stress-induced senescent phenotype in the trabecular meshwork (TM) cells; and that the gradual accumulation of cells with such a proteasome-impaired/senescent phenotype contributes to the pathological changes that lead to increased outflow resistance in the TM. This hypothesis is supported by our preliminary data showing that: 1) chronic oxidative and mechanical stress can induce proteasome failure and a senescent phenotype in TM cells; 2) direct chronic inhibition of the proteasome can lead to a similar senescent phenotype; 3) there is an increase in senescent cells with age in normal TM and; 4) the TM from POAG donors has a significantly higher number of senescent-associated -beta-galactosidase cells than those from age-matched controls. To test our hypothesis, we propose the following three specific aims: SA-1) Evaluate whether chronic proteasome inhibition alone induces cell senescence through activation of the same regulatory pathway as chronic oxidative stress; SA-2) Evaluate whether induction of cell senescence results in pathophysiological changes that lead to increased outflow resistance; and SA-3) Evaluate whether activation of proteasome function can delay the induction of cellular senescence and pathological changes in the TM after chronic oxidative stress. We believe that these studies will provide important insights into possible pathophysiological mechanisms involved in glaucoma. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY016228-01A1
Application #
6969177
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Liberman, Ellen S
Project Start
2005-09-30
Project End
2010-06-30
Budget Start
2005-09-30
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$289,918
Indirect Cost
Name
Duke University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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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
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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
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; 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

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