Diabetes and Metabolic Disorders

Research Projects

David A. 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.

The blood vessels in the brain and retina are different from other vascular beds. These vessels have tight control of what enters or leaves the neural tissue and contribute to the formation of the blood-brain and blood-retinal barriers. Our laboratory is specifically interested in the tight junction complex that contributes to the formation of this 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 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. Our current research focuses on understanding how the blood-retinal barrier normally develops in the retina and how to restore normal barrier properties in diseases like diabetic retinopathy. This research has led our team to develop methods to regenerate normal retinal vascular function in models of diabetes. 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.

Patrice E. Fort, PhD, MS

We seek to understand the molecular mechanisms of diabetic retinopathy using a combination of animal and cell models as well as a biorepository of human ocular samples. The biorepository is used in discovery experiments to identify new elements of the impact of diabetes on normal retinal physiology as well as in the progression of diabetic retinopathy. Among the pathways previously identified, we are particularly interested in intrinsic protective mechanisms and their disruption by diabetes, including the insulin receptor/Akt/mTOR signaling pathway, and the crystallin protein family. Regarding the former, we continuously seek to better understand its regulation which we showed is different from other insulin-sensitive tissues but is required for proper retinal function. For the latter, increased levels of crystallin proteins has been shown to be one of the most consistent effect of diabetes on retinal proteome across species but its role and regulation is still unclear. We have recently uncover new implications in retinal neuroprotection and negative regulation of this function by diabetes, but specific aspects still need to be fully understood.

 

Related Faculty Bios

Dr. David Antonetti

David A. Antonetti, PhD

Roger W. Kittendorf Research Professor of Ophthalmology and Visual Sciences
Professor, Ophthalmology and Visual Sciences
Professor, Molecular & Integrative Physiology
Office: 734-232-8230; Lab: 734-615-3821
Dr. Patrice Fort

Patrice E. Fort, PhD, MS

Associate Professor, Ophthalmology and Visual Sciences
Associate Professor, Molecular & Integrative Physiology
Office: 734-232-8225