UNDERSTANDING THE ROLE OF RETINOL DEHYDROGENASES RDH11 AND RDH12 IN VISION

这个子项目是众多研究子项目之一

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The retinol dehydrogenase RDH12 was identified as a disease-causing gene for Leber Congenital Amaurosis, the earliest and most severe inherited retinal dystrophy. The physiological role of RDH12 is unknown. We hypothesize that RDH12 inactivates toxic molecules produced during oxidative stress in photoreceptors. We also hypothesize that the closely related enzyme, RDH11, has the same function. Bright light induces oxidative stress and lipid peroxidation in photoreceptors, leading to the formation of toxic 4-hydroxynonenal (4-HNE). 4-HNE forms adduct with proteins disrupting important cellular functions. Adducts accumulate in photoreceptors during bright light exposure prior to photoreceptor apoptosis. RDH11 and RDH12 were shown to reduce 4-HNE in vitro and we found evidences that they protect cultured cells and photoreceptors against 4-HNE-induced adduct formation and apoptosis. The following specific aims will allow us to further test our hypothesis. Aim 1: Characterize the catalytic activities of RDH11 and RDH12 towards 4-HNE in vitro and in mouse retina. Aim 2: Determine whether RDH11 and RDH12 are protective against the formation of 4-HNE-protein adducts and apoptosis of photoreceptors in vivo. Aim 3: Test the hypothesis that RDH11 compensates for RDH12 in the mouse retina. If we successfully demonstrate that the physiological role of RDH11 and RDH12 is to detoxify 4-HNE in photoreceptor inner segments, this will have a clinical impact because it will provide a strategy for the treatment of patients with a progressive loss of vision due to RDH12 mutations.