Our aims are focused on advancing current knowledge on the role of peripherin 2 (Prph2), also called retinal degeneration slow (RDS), in outer segment (OS) rim and disc formation, and in understanding the pathogenic mechanisms of PRPH2-associated disease. We use state-of-the-art technologies and our novel knockin mouse models to learn 1) how different mutations in Prph2 lead to different disease phenotypes; 2) what contributes to variability among patients carrying the same mutation; 3) what role the Prph2 partner, rod outer segment membrane protein 1 (Rom1), plays in these events; and 4) how we can shift PRPH2-associated severe phenotypes to milder ones. PRPH2 mutations lead to retinal diseases ranging from retinitis pigmentosa (RP) to a variety of macular degenerations (MD) including pattern dystrophy (PD), which often associates with secondary defects in neighboring tissues such as the retinal pigment epithelium and retinal/choroidal vasculature. In spite of the scientific progress so far, a therapeutic option suitable for clinical testing has not yet been developed. This disappointing outcome is further complicated by the diverse role of Prph2 in rods versus cones, poor genotype-phenotype correlations, vast intrafamilial and interfamilial phenotypic variability, the involvement of multiple tissues in the disease process, and the need for a precise dose of Prph2 to combat the devastating effect of haploinsufficiency. Thus a thorough understanding of Prph2-associated disease mechanisms, an absolute prerequisite for the development of effective therapies, requires precise knowledge of the differential role of Prph2 in rods versus cones and the processes that link photoreceptor defects with subsequent toxic effects in other tissues. Our findings suggest that rod-targeted disease (e.g. RP) arises due to haploinsufficiency while cone-dominant diseases exhibit a more complex and variable pathology associated with gain-of-function or dominant-negative effects. However, little is known about the link between these primary defects in photoreceptors and the blinding secondary sequellae or about what causes intrafamilial phenotypic heterogeneity. For the first time we have generated mouse models that will allow us to address these questions. In addition, we have developed an outstanding team of investigators comprising recognized field leaders in photoreceptor cell biology, with researchers skilled in understanding and evaluating choroidal and retinal vasculature. Our preliminary data support the hypothesis that Rom1 is a key modifier in cases where there is significant within-mutation disease variability.
Aim1 will assess the role of Syn3B interactions with Prph2/Rom1 and in OS trafficking.
Aim 2 will evaluate mechanisms of diversity in Prph2-associated disease phenotype.
Aim 3 will address the role of Rom1 in modulating the disease pathology of Prph2 mutations. In summary, results from this application will facilitate our understanding of the role of Prph2 in rods and cones in health and disease states. Outcomes from these studies will help direct therapeutic strategies to overcome blindness associated with PRPH2.
PRPH2-associated disease phenotypes are complex and multifactorial, involving not just photoreceptors, as has historically been reasoned, but also secondary effects on the retinal pigment epithelium and retinal/choroidal vasculature. Understanding the mechanisms of these complicated disease phenotypes is absolutely critical for the development of treatments and for our understanding of disease mechanisms associated with other genes in which the primary defect is in photoreceptors but the disease phenotype affects multiple tissues. These studies use novel mouse models to directly address these issues in unique ways that are innovative and highly suited to our expertise and tools.
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