Retinal Disease: Molecular Basis and Pathophysiology

PROJECT SUMMARY/ABSTRACT Understanding how a pathogenic mutation leads to disease is extremely important for prognosis, for developing effective treatments and for assessing likely response to treatment. Genes do not act in isolation. Gene mutations typically do not cause the disease pathology themselves - rather, they activate or deactivate biological pathways, affecting a set of molecules whose function results in the manifestation and progression of disease phenotypes. Furthermore, evidence from several groups including our preliminary omics studies suggests that alterations in different sets of molecules may lead to multiple disease phenotypes, further adding to the complexities underlying genetic mutations and their effects. The goal of this application is to delve into this complexity by looking closely at three different disease aspects of the Mfrprd6 mutation, namely, photoreceptor degeneration, hyperopia and fundus spotting, and examine their association with three intermediary phenotypes, aberrant DHA levels, cytoskeletal derangements and immune cell responses. Our approach is to use clinical, functional and biochemical tests to provide a deep characterization of the disease phenotypes and to examine associated cellular changes using single-nuclear transcriptomics and proteomic analyses. These phenotypic and genomics data will be analyzed using computational methods to identify the earliest perturbations in these models, and to determine in proof-of- principle experiments, whether it is possible to manipulate the disease outcomes with nutriceutical and pharmacological interventions. Successful completion of our studies will identify the pathogenic pathways that result in observed disease phenotypes, due to the disruption of Mfrp function, revealing potential therapeutic targets that may play a role in a broad range of retinal genetic diseases with similar phenotypic manifestations. .