Project Number: 8050-51000-101-001-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: May 1, 2019
End Date: May 30, 2024
Objective 1: Determine how diet, the interactions of diet and specific foods/food components with individual/population genetics and/or the microbiome, as well as how etiologic factors including nutrients, metabolites, and enzymes, are related to eye health and the onset, prevalence, and progress of age-related macular degeneration (AMD) and cataract during aging. Sub-objective 1A: Accumulation of AMDf and advanced glycation end products (AGEs) in high-glycemic (HG) fed mice can be arrested or reversed using GLO1 overexpression(GLO1-OE) or low-glycemic (LG) diet, but deletion of Nrf2 will compromise the eyes in the animals. Objective 2: Identify mechanisms by which retina and lens function are maintained throughout life. Sub-objective 2A: To test the hypothesis that specific gut microbiota are related to risk for AMDf and cataract, using microbe transfer and gnotobiotic mice. Subobjective 2B: To test the hypothesis that enhancing autophagic lysosomal proteolytic system (ALPS) will improve protein quality control. Subobjective 2C: To test the novel hypothesis that in order to accomplish the unidirectional process of lens fiber cell denucleation (LFCD), the lens has adopted many of the regulators, including the activation of cyclin dependent kinase (Cdk1) and the Cdk1 autoregulatory loop. Objective 3: Find new biomarkers of eye tissue function using readily available samples, i.e., blood, urine, tears, cornea, skin, for in vivo assessment. Sub-objective 3A: In order to gain more insight into the mechanisms behind the relationships between dietary glycemia, retina and lens phenotypes, AGEs, inflammatory markers, etc. we will identify and quantify the products produced and the changes to metabolism due to the diet in each genotype of animals from Objective 1. We use three platforms to accomplish these analyses. Together, they identify and quantify the broadest array of metabolites. These analyses will also identify many new potential biomarkers in urine and plasma from HG-, LG- mice. Sub-objective 3B: Identification of novel biomarkers of human AMD.
Vision is our most cherished sense. Eyesight, however, deteriorates with age, leading to lowered quality of life among aged populations and increased public health expenditures. While no known cures exist for cataract and dry age-related macular degeneration (AMD), the most prevalent age-related eye diseases, our lab is discovering nutritional interventions that appear to delay onset or progression of these diseases. Micronutrients, including vitamin E, vitamin C, vitamin A, lutein and zinc, have been established as vital to eye health. We have new evidence that limiting intake of certain types of macronutrients, specifically, highly refined grains and highly processed carbohydrates – now a big part of the Western diet – can prolong visual function. We are building on this discovery. Our research will further define relations between diet, genotypes, the microbiome and metabolic products produced in response to dietary carbohydrate. This research will use human data, laboratory models and cell free approaches to find ways to stave off agerelated eye disease and prolong vision. This includes elucidating pathways via which development is regulated and damaged proteins are removed. As people continue to live longer in the United States, it becomes imperative to identify ways to prevent the onset of these debilitating diseases, especially as we know almost all older adults will be affected by cataracts and close to 30 percent of people over 75 years will be diagnosed with age-related macular degeneration.