Thursday, April 25, 2024
4/25/2024
Project Summary / Abstract This project investigates the molecular and cellular mechanisms that govern vertebrate photoreceptor outer segment (OS) structure, a fundamental unsolved problem in photoreceptor cell biology. This basic science knowledge gap severely limits clinical understanding of (and treatments for) blinding diseases in humans and animals caused by mutations that disrupt OS structure. A broad variety of inherited retinal degenerations (IRDs) are caused by mutations that disrupt OS organelle structure. Because normal OS structure is required for healthy vision but is not yet understood, it is essential to advance knowledge of how the many hundreds of membranous disks required by each rod and cone are properly shaped and stabilized. The most longstanding and well-known examples of IRDs triggered by abnormal OS structure are caused by mutations in peripherin-2/rds (P/rds). This proposal builds upon our demonstration in the previous project period that P/rds directly generates membrane curvature, to precisely sculpt the hundreds of membranous disk rims present in rod and cone OSs. This advance provides a clear mechanistic explanation for the general effects of P/rds mutations on OS structure, but leaves open the critical and fundamental questions of how P/rds activity is regulated, and how inherited defects in P/rds generate a diversity of disease phenotypes. Our central hypothesis is that regulation of P/rds function by heterotypic interactions with rom1 and glutamic acid-rich proteins (GARPs) contributes to differences between rod and cone OS disk structures. The research strategy will therefore identify how P/rds works together with rom1 and GARPs to build and maintain normal OS structure, and will investigate the significance of these proteins for rod vs. cone disk architectures and how mutations can disrupt organelle structure to trigger particular retinal diseases. An integrated approach using contributions from human molecular genetics, in vitro biochemistry, in cellulo functional assays, and in situ analyses of engineered vertebrate animal models will be utilized to carry out the research. Specific Aim 1 will elucidate the significance of heterotypic (rom1 and GARP) interactions for P/rds structure, molecular function, and support of OS disk architecture. Specific Aim 2 will identify differential contributions of P/rds to rod and cone structures and viability. Overall, these studies are expected to clarify how normal rod and cone OS disk structures are generated and stabilized by photoreceptor-specific proteins that are essential for human retinal health and vision. This work will also provide an improved mechanistic basis for understanding how pathogenic mutations in P/rds can differentially impact rods and cones to produce a broad heterogeneity of IRDs.
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