1a. Objectives (from AD-416):
1. Determine how specific foods, specific components of foods of particular patterns or dietary intake are related to eye health. 2. Identify nutritional etiologic factors that are causally related to onset, prevalence and progress of age-related macular degeneration and cataract. Design diets, dietary supplements or natural reagents to delay these diseases. 3. Identify mechanisms by which retina and lens function are maintained throughout life.
1b. Approach (from AD-416):
The objectives of the Laboratory for Nutrition and Vision Research are to find nutritional means to diminish the prevalence or delay the onset or progress of age-related eye diseases such as cataract and age-related macular degeneration. These are the major blinding diseases. We approach these objectives using epidemiologic and laboratory techniques. At present we are analyzing nutritional, ophthalmologic and genetic data from about 15,000 people. Studies in the laboratory are oriented to determine the pathobiologic mechanisms that underlie the epidemiologic observations. Thus, we are trying to understand how consuming a diet that provides high levels of readily digested carbohydrate (dietary glycemic index) is related to increased risk for macular degeneration and cataract. We are also trying to understand why antioxidants confer visual benefit. A complementary aspect of this work involves elucidation how the proteolytic machinery specifically, and the protein quality control machinery in general, is related to maintaining proper protein quality within lens and retina cells. Another aspect of this work involves trying to understand how this proteolytic machinery controls tissue formation and integrity and how its function is related to nutrition.
3. Progress Report:
This progress report includes the work of one subordinate project at the HNRCA funded through a Specific Cooperative Agreement with TUFTS UNIVERSITY. For further information and progress report, see 1950-51000-075-02S (Using nutrition and proteolysis to delay age related macular degeneration and cataracts).
1. Dietary carbohydrate intake is related to risk for age related macular degeneration and total body compromise. Age related macular degeneration (AMD) is the leading cause of blindness in America and there are no known means to delay the onset and progress of this disease. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, at Boston, Massachusetts obtained epidemiologic information that indicates that consuming diets that release glucose into the bloodstream more slowly, called lower glycemic index diets, have lower risk for the onset and progress of AMD. Through an animal model developed at the HRNCA we showed that AMD-like lesions are affected by the glycemic index of the diets the animals consumed, and that animals consuming the lower glycemic index diet developed lesions at far slower rates. Further, we have also discovered the underlying mechanism and showed that proteins that get damaged by excess sugars accumulate and become toxic to their cells. This observation explains why so many tissues in the body are damaged by “glycative” stress of higher glycemic index diets. The data point to a crucial need to understand the role and function of sugars in our foods and diet. With slight dietary modification, we predict that over 80,000 people can be spared from AMD.
2. Elucidation of pathways by which damaged proteins are removed. The lens and retina are subject to intense photooxidative stress because they must transmit light and, at least for the retina, are also subject to some of the highest levels of oxygen in the body. Together, the light and oxygen cause extensive damage to the constituents of the cells. The damaged proteins that are caused by this stress are toxic to cells and limit their ability to perform their vision function. Surprisingly, the cells that must handle the debris caused by the photooxidative burden are themselves not replacable as are many other types of cells nonrenewable. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, at Boston, Massachusetts documented the function of two proteolytic pathways and the inter relationship between them. Called the ubiquitin proteasome pathway and the autophagic pathways, these pathways clear damaged molecules, thus permitting continued cellular function. We showed that the pathways interact and that compromise of one, often leads to stress of the other. We have also demonstrated that lutein can prolong many molecular processes in the face of stress. This work will inform about optimal diets to preserve the protein editing capacities of eye tissues and prolong visual function in the face of age-related stresses that compromise vision.
3. Linking calcium metabolism to function of proteolytic pathways and tissue development. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, at Boston, Massachusetts discovered that the ubiquitin proteasome pathway controls lens development. We found novel relations between function of this proteolytic pathway and another proteolytic pathway called the calpains (calcium stimulated proteases). Expression of mutant ubiquitin causes the channels that link lens cells to be defective. This leads to accumulation of calcium, triggering or unscheduled calpain activity and digestion of the tissue. Together this results in cataracts. The data demonstrate for the first time that the ubiquitin and calpain pathways are linked and how that linkage occurs. The findings show how finely tuned the various systems for assuring proper populations of proteins must be in order to foster optimal development and aging.Bian, Q., Gao, S., Zhou, J., Qin, J., Taylor, A., Johnson, E.J., Tang, G., Sparrow, J.R., Gierhart, D., Shang, F. 2011. Lutein and zeaxanthin supplementation reduces photo-oxidative damage and modulates the expression of inflammation related genes in retinal pigment epithelial cells. Free Radicals in Biology and Medicine. 53(6):1298-1307.