Proliferative vitreoretinopathy (PVR) is a fibrotic complication affecting the retina. In PVR, loss of visual acuity, and in severe cases blindness, is caused by contraction of scar tissue that form on the retinal surface. PVR is found in ~50% of posterior segment ocular trauma cases and about 5% of cases after surgical repair of rhegmatogenous retinal detachment. Reliable treatment for PVR is currently unavailable, and therefore, prevention is important. The overall goal of this project is to unravel molecular mechanisms involved in PVR development to identify targets for potential intervention. The trigger for fibrosis such as PVR is sustained presence of myofibroblasts, a cell type specialized ECM deposition and wound contraction. Recent studies show that stiff ECM activates intracellular signaling essential for differentiation of myofibroblasts. Myofibroblasts, in turn, feeds back to further enhances ECM stiffness via aberrant ECM deposition and crosslinking. This positive feedback loop between myofibroblasts and ECM rigidity sustains myofibroblast presence, and its inhibition successfully prevented lung and liver fibrosis in animal models. However, the underlying detailed mechanisms and molecules involved are both tissue and cell type dependent, and the role of this positive feedback loop is yet to be examine in PVR. Past studies show the presence of molecules involved in ECM stiffening in samples from PVR patients. Our preliminary data show two key molecules known to be affected by ECM stiffness, transient receptor potential vanilloid 4 (TRPV4) channel and myocardin-related transcription factor (MRTF), are required for myofibroblast transdifferentiation of retinal pigment epithelial (RPE) and Mller glia cells, two resident cell types that give rise to myofibroblasts in PVR. Further, data also show another molecule regulated by stiffness and known to alter MRTF target expression, TAZ, interacts with MRTF. We propose studies to determine molecular mechanisms activated by ECM stiffness leading to myofibroblast differentiation and PVR.
In Aim1, the effect of ECM stiffening molecules on myofibroblast differentiation and PVR will be examine. Detailed molecular mechanism of regulating MRTF, which is key to myofibroblast differentiation, by TRPV4 and TAZ will be determined in Aim2 and 3, respectively. The project has the potential to uncover key molecular therapeutic targets for the prevention of PVR, and possibly other fibrotic diseases.
Proliferative vitreoretinopathy (PVR) is a fibrotic complication that causes retinal folds and/or traction retinal detachment resulting in loss of visual acuity, and in severe cases, blindness. We propose to study signaling mechanisms involving both cells and the fibrotic extracellular matrix that creates a positive feedback loop that results in PVR. The ultimate aim is to identify key molecules that can become therapeutic targets for the prevention of PVR.
