How Age-Related Macular Degeneration Risk Factors Interact in Disease Development

This project aims to characterize interactions of genetics, age, and diet in age-related macular degeneration risk for a model to use in therapeutics development and testing.

Risk factors for age-related macular degeneration include genetics, age, and diet. Freye Mowat, PhD, plans to investigate how these three factors interact in the development of the disease at different levels of biology. She and her colleagues will examine how the trio of factors affects vision, patterns of gene expression, and metabolic function of the eye. Using lab models of age-related macular degeneration, Dr. Mowat and her colleagues will focus on high dietary glucose, a gene implicated in mitochondrial effects in the disease, and age. They predict that the three risk factors combined will result in the features of age-related macular degeneration in their model, which will allow them to sort out the biological pathways under their influence.

One novel aspect of their work will be its focus on how DNA is regulated by the addition or removal of chemical tags that affect gene availability and expression. This regulation, called DNA methylation, has not been clarified especially in the early stages of the disease. Using their model and assessing the effects of the risk factors separately and together, Dr. Mowat and her colleagues will produce a first picture of these early patterns under the influence of diet, aging, and genetics. They aim to produce a thorough, in-depth model of these effects that researchers can use in developing and testing candidate treatments. Such a model could be used, for example, in testing whether candidate therapies prevent the accumulation of molecular changes associated with this suite of risk factors.

The role of DNA methylation in AMD pathophysiology is poorly understood, partly because human tissue samples are obtained late in disease, or proxy blood-based assessments are used. By performing an unbiased, eye tissue genome-wide methylome analysis integrated with downstream gene expression profiles, we can determine which AMD-associated genes and pathways are undergoing epigenetic silencing in the context of aging and diet risk factor exposures.

The proposed research is highly relevant to human dry age-related macular degeneration (AMD), a prevalent macular disorder affecting predominantly older adults. The dry form of AMD is common, has complex risk factors, and has very limited treatment options at present. Ultimately, our carefully designed, multifactorial model will be used to develop and/or test promising dry AMD therapeutics for future clinical translation.