Mechanistic study and therapeutic development for subretinal fibrosis

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PROJECT SUMMARY Subretinal fibrosis underlies the end-stage pathogenesis of several retinal diseases including age- related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR). Fibrosis results from neovascularization or injuries and is part of the wound healing response characterized by the formation of excessive accumulation of extracellular matrix (ECM) connective tissue. Subretinal fibrosis can generate contractile force, cause scar formation, massive subretinal hemorrhage, and retinal detachment, therefore disrupting retinal structures and eventually leading to legal blindness. The cellular and molecular mechanism of subretinal fibrosis is still unclear, and the clinical treatment for this condition is very limited. Myofibroblast is a predominant cell type that are critically involved in fibrosis. The cellular contribution to myofibroblasts is diverse and heterogenous, with multiple cell types involved. For example, RPE cells contribute to fibrosis through epithelial-mesenchymal transition (EMT), endothelial cells contribute to fibrosis through endothelial-mesenchymal transition (endMT), and macrophages contribute to fibrosis through macrophage-mesenchymal transition (MMT). To fully understand the mechanism of subretinal fibrosis, the role of myofibroblast and the contribution of different cell-types to subretinal fibrosis need to be resolved. MicroRNAs (miRNAs or miRs) are endogenous small molecules which can regulate diverse pathways in different cell types. Several miRNAs, including miR-29, miR-24, and miR-21 have been associated with fibrosis. Our preliminary data showed that miR-24 overexpression inhibits EMT, endMT and fibrosis by regulating TGF-β/SMAD3 and LIMK2/MRTF pathways, suggesting miR-24 could serve as an ideal therapeutic target for subretinal fibrosis by targeting two major pathways in different cell types. The broad goal of this proposal is to elucidate the cellular contribution, identity and function of myofibroblasts in subretinal fibrosis and test the therapeutic potential of miR-24 in subretinal fibrosis. We hypothesize that: (1) myofibroblasts from multiple cell lineages could contribute to subretinal fibrosis; and (2) miR-24, can repress EMT, endoMT and MMT by regulating TGF-β/SMAD3 and LIMK2/MRTF pathways, therefore representing an excellent “one drug/multiple targets” model for treating subretinal fibrosis in AMD and PVR. Two Aims will be pursued: Aim I is to define the function, identity, and origin of myofibroblasts in subretinal fibrosis; and Aim II is to determine the therapeutic potential of miR-24 in subretinal fibrosis. Successful completion of the proposed project will pave the way to study the mechanism and therapeutics of subretinal fibrosis in human AMD and PVR patients.