The long term goals of our research are to unravel the genetic causes of blindness and develop therapeutic approaches to treat these causes. The goal of this proposal is to dissect the mechanism controlling alternative splicing in photoreceptors and to determine the role of alternative splicing in shaping the function of photoreceptor cells. Photoreceptor cells express unique isoforms of ubiquitously expressed genes. In particular, our RNA-seq analyses show an inclusion of smaller exons microexons in the photoreceptor cells. This is prevalent in genes that are crucial for ciliogenesis leading to ou main hypothesis that alternative splicing events in photoreceptors contribute to the generation and function of specialized elaborated cilium, the outer segment. In this proposal, we will generate novel animal models to study the mechanism behind the inclusion of microexons in photoreceptor cells and test the importance of this process for vision. Our proposed studies are aligned with the Retinal Diseases Program of the NEI to Identify the genes involved in both inherited and retinal degenerative diseases (including RP), determine the pathophysiological mechanisms underlying these mutations, and determine new potential therapeutic strategies for treatment such as gene transfer, tissue and cell transplantation, growth factor therapy, and pharmacological intervention. Our proposed studies have an implication on novel therapies such as gene transfer that are currently transitioning into the clinical arena.
This project is aimed at unraveling the mechanism behind alternative splicing that leads to photoreceptor specific inclusion of microexons. Our research will also test the importance of photoreceptor specific microexon in three genes that cause ciliopathies, including blindness in humans.
|Corbin, Deborah R; Rehg, Jerold E; Shepherd, Danielle L et al. (2017) Excess coenzyme A reduces skeletal muscle performance and strength in mice overexpressing human PANK2. Mol Genet Metab 120:350-362|
|Murphy, Daniel; Cieply, Benjamin; Carstens, Russ et al. (2016) The Musashi 1 Controls the Splicing of Photoreceptor-Specific Exons in the Vertebrate Retina. PLoS Genet 12:e1006256|