BLRD Research Career Scientist Award Application

Veterans Health Administration, Decatur PA

Investigators

Abstract

Research in the Kiser laboratory is focused on elucidating mechanisms enabling the first steps of vision and using this information to gain an understanding of retinal diseases affecting veterans with the end goal of developing effective therapeutics. To achieve these objectives, we employ an array of experimental approaches ranging from atomic-level investigations of vision-enabling proteins to the development and characterization of animal models of retinal diseases. Our investigations are focused on gaining insights into retinal disease pathogenesis with the overarching goal of developing disease- modifying therapies, which are currently extremely limited. Our research efforts can broadly be categorized into five general areas, which I elaborate on below. 1) Retinoids and the visual cycle. Major effort is lab is devoted to elucidating the molecular, cellular, and physiological processes that underpin the first steps of vision. The lab is a world leader in the biochemistry and structural biology of a crucial retinoid biochemical pathway operating in the eye known as the visual cycle. We have led efforts to understand retinoid processing by the key visual cycle isomerase, RPE65. We have also made important contributions to understanding the initiation and quenching of signaling by the retinal light receptor known as rhodopsin. 2) Visual cycle modulation. We specialize in a therapeutic approach known as visual cycle modulation that seeks to dampen the activity of the visual cycle with the goal of modifying metabolic processes that are believed to drive retinal diseases including age-related macular degeneration (AMD) and diabetic retinopathy (DR). Our studies range from structure-guided drug design efforts to the testing of lead molecules in pre-clinical animal models. Our studies have succeeded in obtaining compounds with pharmacological properties favorable for translation into human studies. A related interest is in the development of synthetic retinoids for the treatment of retinal diseases. 3) Animal models of retinal disease. The laboratory has made important contributions to developing models of retinal disease including models of both dominant (late-onset) and recessive retinitis pigmentosa. We have used these models to gain important and unexpected insights into disease pathogenesis that have informed therapeutic strategies, including the applicability of gene therapy or genome editing technologies. We have also developed a new tool to interrogate roles of the retinal pigment epithelium in retinal biology and disease. 4) Carotenoid metabolism. We laboratory also invests substantial effort into understanding the metabolism of compounds known as carotenoids that serve both as precursors to the light-sensitive Vitamin A-derivative in the eye, known as 11-cis-retinal, and serve a protective role within the macular region of the retina. We have unique expertise in understanding the metabolism of carotenoids by enzymes called carotenoid cleavage dioxygenases (CCDs). 5) Systems Pharmacology. We also contribute to a collaborative project involving VA investigators that seeks to develop the concept of systems pharmacology for the treatment of retinal diseases such as AMD and DR. The laboratory plays an important role in these projects through our expertise in retinal disease models and clinical pharmacology.