Molecular mechanism underlying late-onset retinal/macular degeneration

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ABSTRACT The goal of this proposal is to understand the molecular underpinnings of the well-characterized monogenic disease, Late Onset Retinal/Macular Degeneration (L-ORD/L-ORMD) that recapitulates the major features of other macular degenerations (MDs) with a drusen forming phenotype including AMD although with later onset. L-ORMD is a dominant macular degeneration characterized by the presence of dark adaptation abnormality as early as in the 30s, drusen-like sub-RPE deposits in the 40s, progressive loss of visual acuity, and neovascularization in the 50s leading to irreversible blindness. The dominant Doyne Honeycomb Retinal Dystrophy (DHRD) and Sorsby's Fundus Dystrophy (SFD) as well as the complex disease AMD are examples of other MDs with drusen phenotype. We identified mutations in the gene C1q-TNF-Related Protein 5 (CTRP5/C1QTNF5) in patients with L-ORMD. CTRP5 is secreted by RPE and interacts with EFEMP1 and TIMP3 whose genes have been implicated in DHRD and SFD respectively. All three proteins are components of the extracellular matrix (ECM) and are substrates of the ECM regulator HTRA1. Likewise, AMD associated proteins CFH and C3 are also members of ECM and substrates of HTRA1. These findings support a role for Bruch's membrane (BrM), a specialized ECM of RPE, in MD pathology. S163R Ctrp5 mutation knock-in (KI) mouse models (KI/Wt & KI/KI) that we developed mimic the human L-ORMD phenotype including sub-RPE deposits and BrM abnormalities. We have also established iPSC-RPE of patients with L-ORMD. Using these models, we will (1) characterize the gene regulatory landscape underlying disease pathology by profiling changes in chromatin accessibility and the transcriptome of retinal cells that are the primary and secondary targets of L-ORMD pathology, (2) analyze the proteome profile of BrM-Choroid of these mice to evaluate changes in ECM composition and matricellular proteins with role in signaling associated with aging and with progression of disease to determine the role of ECM in L-ORMD pathology and (3) validate the molecular networks found to play a role in L-ORMD pathology using model systems. The outcomes of this study have the potential to delineate how the molecular networks in each retinal cell type is individually impacted by aging and by progression of disease, and if the retinal cell types adapt to the chronic cellular stress of disease by modulating the epigenome. The studies proposed will significantly enhance our understanding of not only L-ORMD, but also other late-onset pathologies such as AMD.