Retinal Disease: Molecular Basis and Pathophysiology

Jackson Laboratory, Bar Harbor ME

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Within any given retinal disease, one often observes variability in onset, severity or phenotypic presentation, even among individuals with the same heritable mutation. Although it is generally agreed upon that this variation is largely attributabl to genetic background modifiers, to date only a handful of these have been identified. This is, in part, due to the relatively small number of families available for study with the same gene disruption and the high heterogeneity of the human population. And yet, knowledge of these modifiers may be crucial for a better understanding of the mechanisms underlying the diseases and for discovering key therapeutic targets that may be effective across groups of retinal diseases. Our laboratory has, therefore, focused on identifying such modifiers in mice, where genetic complexity is easier to resolve and what is learned may be applicable to direct translational research for improving eye health in humans. In this proposal, we aim to identify genetic modifiers that modulate photoreceptor degeneration and axial length in four interacting genes: Mfrp, C1qtnf5, Crb1 and Prss56, which our laboratory studied during the past award period. Recent evidence points to intriguing genetic and biochemical connections among these genes. In Aim 1, we will determine shared mechanisms for disease modification of photoreceptor degeneration caused by Mfrprd6/rd6 and Crb1rd8/rd8, focusing particularly upon modifiers such as C1qtnf5-/- and PrckiTvrm258/+ with immune modulatory effects. In Aim 2, we will identify genetic modifiers of axial length to determine the pathway through which Mfrp and Prss56 affect the postnatal development of the eye. Finally, in Aim 3, a global approach of gene profiling will be utilized to identify common sets of dysregulated genes to delineate potential pathways that are shared amongst these genes. At the successful conclusion of the work outlined, we will identify the functional and pathophysiological networks impacted by Mfrp, C1qtnf5, Crb1 and Prss56, and the common pathways that underpin the genetic interactions observed among mutations in these molecules. Identification of common pathways will provide information on how deficits of these encoded genes ultimately lead to the observed disease phenotypes and offer potential therapeutic targets that may reach beyond the effects of the individual molecules themselves.