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Principal Investigator: Shusheng Wang
Organization: TULANE UNIVERSITY OF LOUISIANA
Fiscal Year: 2024
Award: $435,204
Funding agency: National Eye Institute
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.
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