David Antonetti, PhD
Our long-term goal is to contribute to the development of novel treatments to prevent or reverse the debilitating loss of vision from diabetes and stroke. The tight junction complex contributes an essential role in multi-cellular organisms by helping to create defined environments between tissues. Tight junctions create a tight seal between cells controlling the flux of fluids, proteins and even ions across tissue barriers. These barriers provide an essential function in a variety of tissues including the intestine, lung and kidneys. Our laboratory is specifically interested in the tight junction complex in specialized regions of the vasculature that help to create the blood-brain and blood-retinal barrier. The tight junctions that connect the endothelial cells in the brain and retina are needed for normal neural function and contribute to the neurovascular unit. This vascular barrier may be compromised in a variety of disease states. Diabetic retinopathy is the leading cause of visual loss in working age adults and is characterized by increased vascular permeability, leading to edema, or fluid accumulation, in the retina. Our laboratory works to understand the cellular and molecular basis for this change in vascular permeability by exploring the changes in the tight junction complex that controls the blood-retinal barrier. Our laboratory utilizes biochemical approaches such as mass spectrometry, cell biology techniques such as mutational analysis in vascular endothelial cell culture, and transgenic mouse studies in models of diabetic retinopathy, in order to understand the mechanisms by which diabetes alters the tight junctions in the blood-retinal barrier. Much of this research has centered on understanding how growth factors and cytokines signal to the tight junction complex and regulate vascular permeability. Our laboratory was one of the first to identify phosphorylation of junctional protein occludin as a regulator of barrier properties. Our recent studies demonstrate that a transgenic mouse models expressing point mutants preventing this phosphorylation preserves the retinal vascular barrier during diabetes and importantly, prevents vision loss. Future studies will explore the intimate relationship between the retinal blood vessels and neural function to better understand the neurovascular unit. Our research on tight junction protein modification has led us to novel research on the blood-brain barrier. In collaboration with Dr. Dan Lawrence at the University of Michigan, we have explored the contribution of phosphorylation of occludin to blood-brain barrier permeability in stroke. Targeting occludin phosphorylation preserves brain vascular barrier properties and is protective in stroke. These studies may allow us to repurpose drugs as novel therapies to treat patients after a stroke event. Research in our laboratory also explores how we can restore barrier properties in the diabetic retina. These studies make use of an endogenous cytokine, norrin that is required for barrier-genesis of the blood-retinal barrier during development. Our research has demonstrated that norrin can reverse diabetes induced loss of barrier properties and we are currently working to deliver norrin as a therapeutic for diabetic retinopathy and to understand the molecular mechanisms by which norrin acts to promote barrier properties.