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.

Public Health Relevance

A great deal of variability in disease phenotypes is observed among individuals with mutations within the same gene. The onset, severity, and disease expression may be affected as well as the effectiveness of and response to particular therapies. While allelic variation and environmental factors may contribute to this observed variability, it i likely that disease phenotypes are primarily modulated by genetic modifiers. Identification of these modifiers may provide insight into the pathological pathways that are induced and the normal function of the primary gene/mutation. Knowledge of the function of the disease-causing genes and the pathways in which they act may lead to an understanding that is critical in defining therapeutic targets for preventing or mitigating vision impairment and loss.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011996-16
Application #
9301549
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
1998-02-01
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
16
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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