Role of crystallins in the neurodegenerative and neuroinflammatory components of human DR
Strategies to treat retinal neurodegenerations, including diabetic retinopathy, are an area of intensive research. Crystallin proteins have intrinsic neuroprotective properties that are disrupted in animal models of diabetes. We previously demonstrated that the progressive increased expression of alpha-crystallins in the retina of diabetic animals was associated with alterations of the biochemical properties of such proteins leading to significant change in the nature of the protein complexes in which they are involved. Numerous targets have been proposed based on studies in animal models of diabetes but turned out to be ineffective in part due to the lack of confirmation of their potential using human tissues. Thus the overall goal of this proposal is to determine the relevance of observations made in animal models of diabetes to the human pathology using our well characterized and standardized repository of fixed and fresh human ocular tissues. Using this repository we recently discovered that alpha-crystallins are expressed by retinal glial cells of diabetic human donors, while it has been demonstrated that they play a key role in the regulation of inflammation in other neurodegenerative diseases. Taken together, this led us to hypothesize that crystallin could be involved in both the neurodegenerative and neuroinflammatory components of diabetes. Thus the main objective of this project is to characterize the effect of diabetes on retinal crystallins in human diabetic patients, and its conjunction with neurodegeneration and neuroinflammation. The long-term goal is to get a better understanding of their role in the retina in order to define their potential relative to the development of novel therapies to prevent the progression of diabetic retinopathy. Specifically, crystallin levels of expression and localization will be analyzed under normal and diabetic conditions, and association or not with retinopathy. Additionally, the inflammatory response signature will be correlated with the levels of expression and the localization of crystallin proteins. This project will determine normal and pathological retinal cell specificity so that crystallin function in the retina can be better understood and ultimately novel therapies may be developed to manipulate crystallins’ function to preserve vision in persons with diabetes.

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