TGFβ Signaling and the Formation of Cross-Linked Actin Networks (CLANs) in Human Trabecular Meshwork Cells
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Glaucoma is the leading cause of irreversible vision loss and blindness worldwide. One of the major risk factors for glaucoma is increased intraocular pressure (IOP); however there is little understanding of the initial causes of abnormal IOP. Actin cytoskeletal rearrangements known as cross-linked actin networks (CLANs) form at a higher incidence in the glaucomatous trabecular meshwork (TM) cells compared to non-glaucomatous TM cells. The incidence of CLANs is believed to increase the stiffness of TM cells and TM tissue, thereby increasing aqueous humor (AH) outflow resistance and IOP. Even though these actin formations are known to be present, the actual cause of their formation has not yet been elucidated. CLANs can be induced by either transforming growth factor-β2 (TGFβ2) or glucocorticoids such as Dexamethasone (Dex). The primary focus of this research is the TGFβ2 induced CLAN formation and the TGFβ pathways leading to these cytoskeletal rearrangements. Primary human TM cell culture was used to identify whether the Smad or non-Smad TGFβ pathways are the primary path to TGFβ2 induced CLAN formation by testing the ability of various inhibitors to prevent and resolve TGFβ2 induced CLANs. The results of this research will be a novel and critical source of information in the development of therapeutic strategies for the treatment of elevated IOP and glaucoma, and possibly a better understanding of additional factors contributing to the onset of this sight threatening disease.