The cytokine TGF? is a pleotropic morphogen that modulates the tissue repair phenotype and also plays an important role in the development of fibrotic repair pathologies. In the lens of the eye, fibrotic pathologies mediated by TGF? include anterior subcapsular cataracts (ASC) and posterior capsular opacification (PCO). The cellular changes that precede fibrosis in ASC and PCO include an increased proliferation of lens epithelial cells (LECs), which under go an epithelial-mesenchymal transformation (EMT) into myofibroblasts, involving loss of E-cadherin and induced a-smooth muscle actin (aSMA) expression. The long-term goal of this project is to determine the TGF?-mediated signals, which alter the genetic makeup and phenotype of lens epithelial cells during ASC. Using a previously developed rat lens culture model in which exogenous TGF? induces ASC we have shown that treatment with agents that inhibit enzymatic activity of Matrix Metalloproteinase (MMP) family members (MMPIs) suppresses the TGF?-induced cataractous changes. Further preliminary findings suggest the testable hypothesis that MMPIs act to inhibit TGF?-induced EMT and ASC in the lens by suppressing MMP-mediated E-cadherin degradation by shedding. The RSmad, Smad3, is a common effector of TGF? signaling, which has been identified in the lens. However, we have found using two different mouse models that in the absence of SmadS (in Smad3 KO mice) TGF?1 can induce EMT in the lens, demonstrating the involvement of Smad3-independent signaling in ASC formation. Additional findings suggest that the hypothesis that TGF?-induced ASC involves signaling MAP kinase pathways, specifically p38, which act independently of Smad3. To test these hypotheses we will utilize the in vitro TGF?-induced rat lens model of ASC, as well as genetically modified mice, including MMP-2, MMP-9 and SmadS KO mice. The effect of MMPIs on E-cadherin expression and shedding will be further examined using RT-QPCR in combination with laser capture microdissection, western blotting and immunolocalization. The requirement for activated p38MAPK in ASC formation will be investigated in both the in vivo and in vitro models using specific Pp38 kinase inhibitors. These data will aid in defining the TGF?-mediated pathways controlling EMT and fibrosis in ASC. Furthermore, since the genes and signaling mechanisms in ASC formation are similar to those which occur in other fibrotic diseases and cancer, the information gained from these studies in the lens may also have relevance to these disease entities. ? ?

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
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Mcmaster University
Zip Code
L8 3-Z5
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