Generation of immunoreagents for studies of CACNA2D4-related inherited retinal dystrophies

About This Grant

Project Summary CACNA2D4 is the gene encoding a2d-4, an extracellular protein that is expressed primarily in the retina. Variants in CACNA2D4 are linked to a spectrum of inherited retinal disorders (IRDs) including cone dystrophies and retinitis pigmentosa. Despite clear evidence from human genetics and studies of knockout animals that a2d-4 is required for vision, it remains an understudied protein. The lack of tools to pinpoint the subcellular localization and modify the function of a2d-4 represents a major hurdle to understanding its role in IRDs. The goal of the proposed research is to develop antibody-based strategies to investigate the cellular functions of a2d-4 in normal and diseased states of the retina. We will use innovative approaches to generate renewable monoclonal antibodies and nanobodies that specifically recognize a2d-4 for use in electron and super-resolution light microscopy or to disrupt the interactions of a2d-4 with specific protein partners. The expected outcomes of the proposed research will contribute to the Pharos mission by shedding light on the localization and function of an understudied ion channel protein. The broader impact of this research is the discovery of mechanisms underlying a2d-4 function that could be targeted in novel disease-modifying therapies.