Restoration of Structure and Function in the Diabetic Cornea

Project Summary/Abstract Objective/Hypothesis. Diabetes is expected to reach epidemic levels by 2030. Despite the prevalence of diabetic retinopathy, many adult diabetic patients develop visually disruptive corneal complications, including impaired wound healing and corneal neuropathy. Unfortunately, treatment for diabetes-induced damage to the cornea remains severely limited to strict glycemic control. Our objective is to investigate a promising peptide-based combination therapy that effectively targets hyperglycemia-responsive circuits in the cornea. By doing so, we hypothesize that Tβ4/VIP combination treatment can prevent high glucose-induced damage to corneal structure and function. In addition, we examine one such responsive circuit – the DDR-TRP axis – a novel pathway that has yet to be explored in the cornea. Specific Aims. This proposal intends to: 1) establish the therapeutic role of Tβ4 and VIP as a combination treatment against diabetes-induced corneal complications; and 2) elucidate the DDR-TRP axis under hyperglycemic conditions. Study Design. Our experimental approach is designed to include both in vitro and in vivo cell-specific analyses. In vitro assessments are focused on corneal epithelial cells and stromal fibroblasts complemented by extensive, comprehensive in vivo assessments that include morphological changes to the epithelium, stroma, epithelial-stromal interface, endothelium, changes in corneal nerves and tear film, AS-OCT, endothelial cell density measurements, fibroblast differentiation, and phenotypic profiling to distinguish between keratocytes, fibroblasts, myofibroblasts, immature/mature dendritic cells, monocytes/macrophages, and neutrophils. In vivo studies include the use of two (2) type 1 diabetic mouse models (STZ-induced and spontaneous Akita) to account for any potential effects due to STZ exposure and will assess changes in corneal structure and function, including corneal integrity and barrier function, sensitivity and innervation, inflammation, and wound healing; all of which not only focus on improved disease outcome but mechanistically examine the role of the DDR-TRP axis and how Tβ4/VIP therapeutically regulates this axis. Impact. Overall, the studies proposed seek to delineate a newly identified mechanism of diabetes-induced damage while providing key preclinical evidence for the development of a novel therapeutic approach with robust translational relevance and potential for significant impact on diabetic corneas.