1. Molecular mechanisms of secondary cataract
Extracapsular cataract surgery leaves the lens capsule mostly intact, which permits implantation of an intraocular lens (IOL). This procedure often leaves behind epithelial cells in the remaining anterior and equatorial capsule, which in time, proliferate and migrate to the posterior capsule. This aberrant growth of epithelial cells, together with transdifferentiation into a mesenchymal phenotype (EMT), leads to posterior capsule opacification (PCO). The lens capsule is a basement membrane secreted by epithelial cells, and like other basement membranes, it accumulates advanced glycation endproducts (AGEs) with age. We are investigating biochemical and molecular mechanisms by which capsule AGEs promote PCO.
2. Molecular mechanisms of protein crosslinking in the lens
Lens proteins undergo disulfide and non-disulfide crosslinking during aging. Such crosslinkings are associated with protein aggregation, insolubilization, light scattering and loss of lens accommodation. While disulfide crosslinking is well studied, the biochemical nature and the mechanism of formation of non-disulfide crosslinking are poorly understood. We are testing a hypothesis that non-disulfide covalent crosslinking of proteins in the lens could arise from glycation-mediated crosslinking of the complexes that are formed between α-crystallin and its chaperoned proteins, which leads to the formation of high molecular weight proteins and protein insolubilization during lens aging. We are also determining whether crosslinking of α-crystallin-client proteins by glycation has a direct relationship with high-molecular-weight protein accumulation in aging lenses. We are testing a novel small molecule against AGE-mediated protein crosslinking and the loss of resilience (presbyopia) in aging lenses.
1. Indoleamine 2,3-dioxygenase in diabetic retinopathy
Inflammatory cytokines are elevated in the eyes of diabetic patients and experimental diabetic animals, pointing to a role for inflammation in diabetic retinopathy. Inhibition of retinal lesions, such as acellular capillary formation and leukostasis in diabetic animals by treatments that suppress inflammation lends strong support to this notion. However, the biochemical mechanisms by which inflammatory cytokines induce pathological changes in the diabetic retina are poorly understood. Our recent studies show that the indoleamine 2,3-dioxygenase (IDO) initiated kynurenine pathway is upregulated in human diabetic retinas and that kynurenine pathway-derived cytotoxic kynurenines induce apoptosis in human retinal endothelial cells. We are investigating the hypothesis that activation of the kynurenine pathway in the glia generates cytotoxic kynurenines that induce apoptosis in retinal capillary cells. We are also testing the ability of kynurenine pathway inhibitors to block formation of cytotoxic kynurenines and inhibit apoptosis of capillary cells.
2. Retinal ganglion cell protection in glaucoma by Peptains
Glaucoma affects more than 60 million people worldwide, and nearly 8 million people have been blinded by this disease. It is a heterogeneous group of disorders that lead to a progressive optic neuropathy and ultimately blindness. Axonal degeneration and death of retinal ganglion cells (RGC) are primary reasons for vision loss in glaucoma. Several lines of evidence suggest that RGC death occurs by apoptosis. We have been testing Peptains (peptides derived from small heat shock proteins) that exhibit robust anti-apoptotic properties against retinal ganglion cell death in chronic and acute animal models for glaucoma.
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