Diabetic Keratopathy and Aging

Diabetes mellitus is a global public health problem characterized by elevated blood glucose levels. The
prevalence of diabetes has now reached pandemic levels (10.5% worldwide), and the incidence rises each year with increasing medical expenditure and significant morbidity and mortality. Diabetes affects multiple organs including the eye. Diabetic keratopathy (DK) is one of most common ocular complications associated with diabetes and is characterized by reduced corneal sensation, delayed corneal wound healing, chronic corneal inflammation, and increased susceptibility to corneal infections, ultimately leading to vision loss. The severity of DK increases with age and the duration of diabetes. Similarly, aging is a physiological condition associated with greater corneal complications in diabetic patients. Both diabetes and aging together cause loss of corneal function and integrity. However, the underlying mechanisms behind diabetic keratopathy and its association with aging are not fully understood. In this proposal, we will investigate the intersection of diabetes and aging using a highly tractable and versatile zebrafish model of DK. We will study gene and protein expression changes induced by diabetes and aging together in juvenile, young, and aged adult zebrafish corneas exposed to glucose over different lengths of time, and how these changes correlate with corneal wound healing in a well-validated zebrafish corneal injury model. Recent studies suggest that mTOR signaling plays a key role in corneal wound healing. We hypothesize that increased expression of mTOR signaling is associated with DK and will study mTOR signaling in diabetes and aging, and how changes to mTOR signaling impact corneal wound healing. We
will use both cutting-edge and conventional molecular methods including RNA-seq, mass spectrometry, flow cytometry, confocal microscopy, qRT-PCR, Western blot, and immunohistochemistry for the proposed experiments. This research proposal will provide novel molecular insights into the respective roles of diabetes and aging in DK, and identify potential targets to develop effective and safe therapeutic drugs to treat DK and prevent permanent vision loss in humans with diabetes.

Grant Number: 5P20GM121176-09
NIH Institute/Center: NIH
Principal Investigator: Praveen Balne