David A. Antonetti, Ph.D.
Research Projects
Our long-term goal is to contribute to the development of novel treatments to prevent or reverse the debilitating loss of vision from diabetes.
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 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 rat and 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. This research has led us to the identification of specific phosphorylation events that are necessary to regulate the dynamic movement of tight junctions from the cell border to the cell interior. Further, we have identified specific signaling molecules necessary for induction of vascular permeability and have successfully developed small molecule inhibitors that control or prevent both growth factor and inflammatory cytokine induced permeability. Currently, these inhibitors are under development as novel therapies to treat macular edema.
The blood-brain and blood-retinal barrier are different from many of the other cell types that form tight junctions. The endothelial cells that line vasculature in the brain and retina require unique signals from the neural tissue to induce the formation of the tight junction complex. Glucocorticoids have been used to treat edema in the brain and retina and we have shown that these steroid hormones act to induce expression of tight junction genes through a novel enhancer element, in other words, a unique region of DNA that helps control gene expression. Research in our laboratory now focuses on understanding the mechanisms by which glucocorticoids induce expression of the tight junction genes and promote assembly of the tight junction complex and whether a similar system is employed in normal development of the blood-brain and blood-retinal barrier. Ultimately, these studies may provide a path for the development of therapies to restore the blood-neural barrier in a variety of diseases including diabetic retinopathy or brain tumors.
