Approximately one in three U.S. adults over 19 years of age (estimated 79 million people) has prediabetes. Given the marked increase in childhood obesity, this trend appears to be sustained. Slow corneal healing, loose epithelial adhesion, corneal nerve fiber damage, and persistent epithelial defects characterize a condition that affects a high percentage (up to 70%) of individuals with diabetes, and puts the cornea at risk for complications arising from accidental injury or ophthalmic procedures such as contact lenses, vitreous surgery, LASIK and retinal photocoagulation. We will use diet-induced obesity and full thickness corneal epithelial abrasion in C57BL/6J mice for studies in vivo, and human corneal epithelial cells for studies in vitro. Our most recent data in vivo reveal that 10 week old mice fed a high fat diet for 5 weeks show systemic inflammation with increased proinflammatory cytokines in blood as well as leukocyte activation and infiltration into adipose tissues. At 5 weeks of high fat diet, there is little evidence of hyperglycemia or insulin resistance. These mice exhibit significant reductions in nerve density in the epithelial branches of the corneal nerves, and when challenged, they exhibit abnormal wound healing after corneal abrasion with reduced regeneration of damaged corneal nerves.
Specific Aims : 1) Determine changes in the cornea and changes in the healing response to corneal epithelial injury induced by feeding mice an obesogenic diet, and assess the reversibility of these changes following diet reversal from the obesogenic diet to an optimum chow diet. Hypothesis: Pathologic changes occur in the cornea in the early stages of diet-induced metabolic syndrome, and normal corneal function is not fully restored upon diet reversal. 2) Determine if diet-induced systemic inflammation contributes to the detrimental changes in the cornea. Hypothesis: Diet-induced inflammation is a major contributor to the corneal pathology that occurs in obesity. 3) Analyze the benefit for diet-induced corneal healing dysfunction of specific interventions conceptually derived from the studies of corneal wound healing and diet-induced corneal dysfunction.
This application will study the importance of inflammation to healing of wounds in the surface of the eye, and analyzes the effects of diet-induced obesity on corneal integrity and wound healing. Of particular interest are the cascades of adhesion molecules, cytokines, chemokines and emigrating cells that are critical for maintenance of corneal integrity and from which therapeutic concepts can be derived for treating the corneal dysfunction resulting from diet- induced obesity and the accompanying metabolic syndrome.
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