Mouse Models for Subretinal Fibrosis

To generate robust, well-characterized subretinal fibrosis mouse models and gain insights into pathways that lead to the disease characteristics.

Tissue damage in the back of the eye may lead to the formation of scar tissue or fibrosis that causes vision impairment. We describe here two new genetic models that develop subretinal fibrosis, a common complication of wet AMD. We will test the hypothesis that RPE dysfunction caused by aberrant cell-cell contact leads to cellular defects that result in subretinal fibrosis in two mouse models. Standard methods such as functional/clinical phenotyping, histology, immunohistochemistry, and biochemical assays, as well as cutting-edge molecular methods including single nuclear RNA-seq, and spatial metabolomic/proteomic, will be used. In Aim 1, longitudinal studies to identify structural and associated cellular and molecular changes that occur as a result of the mutations will be done. In Aim 2, we use genetic modifiers that moderate the retinal phenotypes in order to gain insights into its disease pathways.

Detailed analysis of the course of events and cellular changes that precede subretinal fibrosis will identify druggable targets, and our novel models will serve as a resource for the development of therapeutics. Comprehensive consideration of the disease presentation together with the cellular changes at the transcriptomic, metabolomic, and proteomic levels will provide an unbiased look at what might be causing the disease and therefore what areas to target.

At the successful conclusion of the studies outlined, we will learn the progression of subretinal fibrosis in the models, and if neovascularization is an initiating factor and determine the cellular changes that are associated with the disease manifestations. Pharmacological intervention and their effects on the disease progression will provide information about therapeutics efficacy, window of opportunity, and whether the disease observed in the Ctnna1 and Lratd2 models is amenable to the particular drugs used.