Project Summary/Abstract
Neurodegeneration is ultimately the main driver of vision loss in retinal diseases including Diabetic retinopathy
(DR) and glaucoma. Neuronal cell death and glial activation and the associated neuroinflammation are widely
recognized as central aspects of the pathophysiology of these diseases; however very few treatment options
exists to control these mechanisms involved in early stages of these diseases. While anti-VEGF is a powerful
new treatment option for the late stages of DR that are proliferative diabetic retinopathy and macular edema,
there are still no therapies available to prevent early alterations of the neuroretina. aA-crystallin is a chaperone
protein, whose protective function, is highly regulated by its phosphorylation on the T148 residue. There is a
fundamental gap in our knowledge regarding the molecular mechanisms by which it promotes the survival of
retinal cells and how those mechanisms are controlled by its phosphorylation on T148. The long-term goal of
this research is to determine how the protective potential of aA-crystallin can be harnessed to reduce or
prevent retinal neurodegneration. The objective of this project is to identify the molecular mechanisms by
which the function of aA-crystallin protein is modulated by its phosphorylation on T148. Emerging from our
preliminary data and previously published work, the central hypothesis guiding this project is that
enhancement of aA-crystallin function through positive modulation of its phosphorylation on T148 residue can
prevent or reduce DR pathophysiology. The rationale for the proposed research is that enhancement of this
intrinsic protective pathway has demonstrated promise for the modulation of metabolic stress-induced
neuroinflammation and neurodegeneration. This hypothesis will be tested by pursuing 2 specific aims: i)
Determine the cell specific mechanisms of the therapeutic potential of the functionally enhanced aA-crystallin
T148D against DR, and ii) Determine the mechanisms of regulation of phosphorylation of aA-crystallin on
T148. Both aims will be concurrently pursued and will support each other, as aim 1 will establish the
therapeutic potential of the functionally enhanced mutated protein and its cell-specific impact, while aim 2 will
identify the cell-specific mechanisms of regulation of this phosphorylation and how they are affected by
diabetes. Altogether this research project will identify and characterize the mechanisms of regulation of the
neuroprotective function of aA-crystallin and how they can be targeted in neurodegenerative diseases,
potentially leading to the development of approaches for utilizing this intrinsic protective pathway to promote
retinal cell survival and control neuroinflammation in chronic neurodegenerative conditions and, thereby,
preserve visual function.
Key terms
AlphaA-crystallins, diabetic retinopathy, intrinsic protective mechanisms, phosphorylation, kinase