Diabetes Microvascular Research
Sayon Roy, PhD, FARVO, Professor of Medicine and Ophthalmology
Vascular basement membrane thickening is a prominent and characteristic lesion of diabetic retinopathy. Excess synthesis of basement membrane components in diabetes is a critical, pathogenetic event in the development of vascular basement membrane thickening and complications of diabetic retinopathy. Having shown that the mRNA level of basement membrane components fibronectin, collagen IV, and laminin are increased in diabetic retinas, we have used antisense oligonucleotides and siRNAs, powerful molecular biological tools, to downregulate specific gene expression with beneficial effects.
Additionally, we are studying whether increased lysyl oxidase (LOX) expression and activation triggered by high glucose/diabetes compromises basement membrane function. Specifically, we are investigating whether excess LOX promotes retinal capillary permeability and increases vascular cell death in diabetic retinopathy. Importantly, our current studies suggest inhibition of high glucose-induced LOX overexpression can reduce cell monolayer permeability. Studies conducted using animal models of diabetic retinopathy and in patients with diabetic retinopathy indicate that LOX expression is significantly elevated and may contribute, at least in part, to retinal vascular lesions associated with diabetic retinopathy.
In another project, we are currently investigating whether connexin 43 (Cx43) downregulation and subsequent altered cell-cell communication triggered by high glucose/diabetes leads to cell death and breakdown of vascular homeostasis in the retinal capillaries in diabetic retinopathy. Our previous studies have shown that high glucose reduces Cx43 expression in retinal vascular cells and compromises gap junction intercellular communication. Thus, the working hypothesis is that high glucose reduces Cx43 expression, triggers vascular cell death, a prominent and early lesion associated with the development of diabetic retinopathy, which in turn, reduces cell-cell communication in the retinal vascular cells and ultimately disrupts vascular homeostasis. Retinal vascular cell death is known to occur by apoptosis but it is unknown how apoptosis is triggered during the development of diabetic retinopathy. Findings from our studies suggest that communication between vascular cells, that is endothelial cell-endothelial cell, endothelial cell-pericyte, and pericyte-pericyte is essential for their survival, and that disruption in cell-cell communication may trigger apoptosis and interfere with their role to form a functional unit via the connexin channels in cell junctions.
We are also investigating the hypothesis that high glucose-induced mitochondrial dysfunction promotes retinal vascular cell death and ultimately retinal function. Our approach is to inhibit mitochondrial fission genes and upregulate mitochondrial fusion genes. Additionally, we plan to facilitate autophagy and promote mitochondrial connexin 43-mediated activity. The proposed project is expected to identify novel mechanism(s) underlying retinal vascular cell loss involving mitochondrial abnormalities, and thus provide insight into potential strategies to prevent these abnormalities related to vascular cell death in diabetic retinopathy.
Although our primary focus is to understand the pathogenesis of diabetic retinopathy and develop novel treatment strategies, we also work on other diabetic microvascular complications, glaucoma, and the aging eye.