Principal Investigator: Shin-Ichiro Imai (WashU Developmental Biology)
Collaborator: Rajendra Apte (WashU Ophthalmology & Visual Sciences)
Retinal neurodegeneration encompasses a broad spectrum of diseases such as retinitis pigmentosa and age-related macular degeneration (AMD), whose end results are usually loss of viable photoreceptor (PR) neurons. Recently, there has been a significant interest in the role of NAD+ biosynthetic processes and its dynamic regulation in the pathogenesis of retinal neurodegenerations. The proposed research will explore the interesting connection between the role of NAD+ biosynthesis, particularly mediated by nicotinamide phosphoribosyltransferase (NAMPT), the key NAD+ biosynthetic enzyme in mammals, and the regulation of photoreceptor neuron survival and retinal degenerations. By using genetically engineered mice, we have already obtained preliminary results suggesting the critical role of NAD+ biosynthesis in the regulation of PR energetics and survival. We have also found that administration of nicotinamide mononucleotide (NMN), a key building block of NAD+, can ameliorate the impairment of PR function and prevent retinal neurodegeneration. Based on these preliminary results, we hypothesize that the impairment of NAD+ biosynthesis contributes to the pathogenesis of retinal neurodegeneration and also that restoring NAD+ production in the retina by NMN administration can treat retinal neurodegenerative diseases. A great advantage of this proposal is its direct application to a broad spectrum of neurodegenerative diseases, given the importance of NAD+ as a key co-factor in photoreceptor neurons and the ‘translational readiness’ towards clinical trials.