Epithelial-mesenchymal transition (EMT) has been shown to play an important role in the fibroses of multiple organs and tissues, including the ocular lens, where it contributes to both anterior subcapsular cataracts (ASC) and posterior capsular opacification (PCO), also known as secondary cataract. Increased proliferation of lens epithelial cells (LECs), and EMT of LECs into myofibroblasts, involving a loss of the cell-cell adhesion molecule E-cadherin and an induction in ?-smooth muscle actin (?SMA) expression are early events in both ASC and PCO. Transforming growth factor beta (TGF?) is a pleotropic morphogen that has been shown to induce the EMT of LECs and subsequent formation of ASC, as well as, PCO. Using a previously developed rat lens culture model in which exogenous TGF? induces ASC we have shown that treatment with inhibitors to the matrix metalloproteinases (MMP), specifically MMP-2 and MMP-9, suppresses TGF? -induced cataractous changes, including EMT. Studies from the previous grant period further show that these two MMPs likely work cooperatively and/or redundantly in the development of these cataracts. For example, using a model of ASC involving the delivery of Ad TGF? to the eye we have shown that MMP-9 KO mice develop cataracts, albeit they are delayed compared to wild-type mice. Thus, inhibiting both MMPs may be required to prevent EMT and subsequent cataractogenesis. The potential mechanism by which these MMPs mediate EMT and cataract formation was identified during the previous funding period and involves disruption of E-cadherin. Preliminary data suggests that disruption and shedding of E-cadherin results in downstream signaling events linked to EMT including nuclear translocation of ?-catenin and the myocardin-related transcription factor (MRTF-A). However, the requirement for these signaling intermediates in ASC and PCO and how MMPs are involved is not known. In the current application we investigate these TGF? -mediated signaling pathways using multiple ex vivo and in vivo models of ASC and PCO. In addition, we outline experiments that will directly determine the unique and/or cooperative roles of MMP-2 and MMP-9 in ASC formation. Ultimately, our goal is to define the TGF? - mediated pathways controlling EMT and fibrosis in ASC and PCO in order to design therapeutics for mitigating these diseases.

Public Health Relevance

Loss of transparency of the lens, or cataract, is the leading cause of blindness worldwide despite the availability of effective surgery in developed countries. Extracapsular cataract extraction is the most frequently performed surgical procedure in North America, costing over 3.5 billion dollars each year, and can frequently lead to complications such as the development of secondary cataract (posterior capsular opacification (PCO). Thus, an understanding of the cellular and molecular mechanisms regulating the normal and pathological differentiation of the lens is necessary in order to develop therapeutic strategies for the treatment and/or prevention of cataracts. In the proposed research we will investigate the cell signaling mechanisms responsible for two fibrotic cataracts, anterior subcapsular cataracts (ASC) and PCO and further determine how these mechanisms can be inhibited. Specifically we will focus on those pathways mediated by transforming growth factor beta (TGF?) and the matrix metalloproteinases (MMPs) since both of have been implicated in these cataracts. Ultimately, it is hoped that the data obtained from the proposed studies will lead to therapeutic strategies for mitigating cataract formation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY017146-06
Application #
8188198
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
2006-03-01
Project End
2016-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
6
Fiscal Year
2011
Total Cost
$242,661
Indirect Cost
Name
Mcmaster University
Department
Type
DUNS #
207510108
City
Hamilton
State
ON
Country
Canada
Zip Code
L8 3-Z5
Padwal, Manreet; Siddique, Imad; Wu, Lili et al. (2017) Matrix metalloproteinase 9 is associated with peritoneal membrane solute transport and induces angiogenesis through ?-catenin signaling. Nephrol Dial Transplant 32:50-61
Boswell, Bruce A; Korol, Anna; West-Mays, Judith A et al. (2017) Dual function of TGF? in lens epithelial cell fate: implications for secondary cataract. Mol Biol Cell 28:907-921
Taiyab, Aftab; Korol, Anna; Deschamps, Paula A et al. (2016) ?-Catenin/CBP-Dependent Signaling Regulates TGF-?-Induced Epithelial to Mesenchymal Transition of Lens Epithelial Cells. Invest Ophthalmol Vis Sci 57:5736-5747
Korol, Anna; Pino, Giuseppe; Dwivedi, Dhruva et al. (2014) Matrix metalloproteinase-9-null mice are resistant to TGF-?-induced anterior subcapsular cataract formation. Am J Pathol 184:2001-12
Gupta, Madhuja; Korol, Anna; West-Mays, Judith A (2013) Nuclear translocation of myocardin-related transcription factor-A during transforming growth factor beta-induced epithelial to mesenchymal transition of lens epithelial cells. Mol Vis 19:1017-28
West-Mays, Judith A; Pino, Guiseppe; Lovicu, Frank J (2010) Development and use of the lens epithelial explant system to study lens differentiation and cataractogenesis. Prog Retin Eye Res 29:135-43
Morarescu, Diana; West-Mays, Judy A; Sheardown, Heather D (2010) Effect of delivery of MMP inhibitors from PDMS as a model IOL material on PCO markers. Biomaterials 31:2399-407
Nathu, Zahra; Dwivedi, Dhruva J; Reddan, John R et al. (2009) Temporal changes in MMP mRNA expression in the lens epithelium during anterior subcapsular cataract formation. Exp Eye Res 88:323-30
Robertson, Jennifer V; Nathu, Zahra; Najjar, Anas et al. (2007) Adenoviral gene transfer of bioactive TGFbeta1 to the rodent eye as a novel model for anterior subcapsular cataract. Mol Vis 13:457-69
West-Mays, Judith A; Pino, Giuseppe (2007) Matrix Metalloproteinases as Mediators of Primary and Secondary Cataracts. Expert Rev Ophthalmol 2:931-938

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