TGFB signaling as a therapeutic target in cataract and PCO

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PROJECT SUMMARY A core goal of the Lens and Cataract Program of the National Eye Institute is the prevention and treatment of cataract. The ocular growth factor TGF¿ is involved in the development of anterior subcapsular cataracts (ASC) and of posterior capsule opacification (PCO), vision-impairing conditions in which both fiber differentiation and epithelial-to- mesenchymal transition (EMT) of lens cells are pathologically upregulated. Although it is well established that TGF¿ induces EMT in lens cells in vitro and in vivo, its role in the fiber-like changes associated with PCO and ASC are unknown. We have developed an innovative model system to study growth factor-mediated signal transduction in the lens, dissociated cell- derived monolayer cultures of primary embryonic chick lens cells (DCDMLs). In this application, we show that DCDMLs are the first culture system in which the ability of TGF¿ to induce EMT as well as fiber differentiation can be studied, providing an unprecedented opportunity to identify the molecular mechanisms that govern these two cell fates and a novel system to discover potential anti-PCO/ASC drugs. The use of small molecule tyrosine kinase inhibitors as targeted therapeutics has revolutionized the treatment of certain cancers. We have discovered that at clinically used concentrations, one such inhibitor blocks both the EMT- and fiber-like changes downstream of TGF¿ in DCDMLs, even after a single, 1 hour treatment. These findings raise, for the first time, the possibility that a well-tolerated small molecule kinase inhibitor could be used to combat both of the pathological fates of lens cells that cause ASC and PCO. The aims of the proposed studies are to understand the mechanistic basis of the effects of this compound, discover other potential anti-PCO/ASC therapeutics using a novel small molecule kinase inhibitor screen, and test these compounds in established ex vivo models of human lens cell fibrosis. This work will elucidate the signal transduction pathways by which TGF¿ enhances EMT and fiber differentiation in lens cells, and open up a novel approach for the prevention of PCO and ASC. Moreover, it will potentially provide new applications for drugs that have, or are in the process of acquiring, FDA approval for human use.