D'Amore, Patricia Ann, PhD
Notch-mediated cell-cell interactions in the pathophysiology of diabetic retinopathy
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Complications, Complications\Ocular, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Transcriptional Regulation
Type of Grant: Innovation
Project Start Date: July 1, 2012
Project End Date: June 30, 2014
Many patients with diabetes develop vascular abnormalities in their retinas, a disease referred to as diabetic retinopathy, which can lead to vision impairment and blindness. Dr. Patricia D'Amore and her colleagues propose to investigate the role of a signaling pathway, called the Notch pathway, in this condition. They will do so by studying human eye tissue removed in the course of surgery to prevent vision loss in diabetic patients. They will also apply a novel technology that allows for analysis protein-protein interactions- the new technique is called BLINC. Notch receptors and the proteins that bind to them allow cells to communicate with each other through close range interactions and it is thought that changes that occur in diabetes could interfere with this. Cells use these cues from neighboring cells as useful information to make decisions regarding their behavior. D'Amore proposes to characterize the cell-cell interactions mediated by the Notch pathway and to determine whether this communication is affected by a diabetic environment. This research may lead to the identification of novel therapeutic targets for the diabetic retinopathy as many drugs that modulate Notch signaling are currently under development for other human conditions.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This research project address the problem of diabetic retinopathy, a serious complication of diabetes and a leading cause of vision loss in working-aged Americans. Clinical and experimental observations indicate that interactions between endothelial cells (ECs) and pericytes, the two cell types that form capillaries, are central to the integrity and function of the retinal vasculature. Loss of pericytes in background diabetic retinopathy is temporally associated with endothelial dysfunction as well as with the onset of new vessel growth, the proliferative phase of diabetic retinopathy.
A central hypothesis of our research is that Notch signaling regulates cellular and molecular processes essential for microvascular differentiation and stability. Basement membrane thickening and pericyte loss are early changes associated with the development of diabetic retinopathy and these events could disrupt Notch signaling, which depends on the juxtaposition of cellular membranes. To test this hypothesis, we are establishing a cell culture system that will allow us to investigate pericyte/endothelial cell interactions mediated by the Notch receptor and its ligands and examine whether a diabetic environment affects these interactions. To achieve this goal, we are using traditional vascular cell co-culture methods, novel technologies that allow for imaging of protein-protein interactions across cellular interfaces, and analyses on human tissues from diabetic patients.
The use of novel technologies for the study of Notch/ligand interactions will allow us to image and quantify interactions of vascular cells in an unprecedented manner and specifically determine how such interactions are impaired in the context of diabetic retinopathy. This research may define new molecular targets and approaches for treatment of this currently untreated and understudied complication of diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
I would explain that the vision problems that are associated with diabetes develop over a long time. Even though the individual may had diabetes for many years during which they had no vision issues, the elevations in glucose that a diabetic person experiences (more or less, depending on their level of control) causes injury to the cells of the smallest blood vessels, the capillaries. Capillaries consist of two cells types, the endothelial cell that forms the lining of the vessel and the pericyte, which lies against the outside of the capillary. With enough injury one of the cell types, called the pericyte, may be lost. Observations in animal models of diabetes as well as in diabetic patients indicate that endothelial cells and pericytes interactions are necessary to keep the capillary healthy and well functioning. When the pericyte is lost, the vessel becomes dysfunctional and may even begin to grow.
Although we know that the interaction between these two cell types is important, we do not fully understand the nature of the communication between them that is disrupted when the pericyte dies. Our project aims to clarify the molecules involved in keeping capillaries stable and functioning. In that way we can determine which pathways might be disrupted in diabetes. This information may allow the development of therapies to block the disturbance of particular pathways or to restore them to normal in disease process.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I was trained as a vascular biologist. During a postdoctoral fellowship at Johns Hopkins I became aware of the fact that many ocular pathologies involve dysfunction and/or growth of blood vessels- with diabetic retinopathy one of the most common and vision threatening. For over thirty years my research focus has focused on the vasculature with a focus on the retina. I have been interested both in the nature of the interactions between pericytes and endothelial cells, which make up capillaries, during the development of the vasculature as well as in pathologies.
My group has contributed significantly to how these cells interact during the formation of new vessels. However, much less I known about the nature and role of how these cells interact in the adult under normal and disease conditions. Because we know that endothelial cells and pericytes make physical contact, and because Notch requires physical contact between the signaling cells, we have become very interested in the potential role of Notch signaling in the adult vasculature. This award will allow us to expand our research efforts into this area.
In what direction do you see the future of diabetes research going?
Because diabetes is on the rise, particularly Type II diabetes, and diabetes research as a whole is understudied, more studies are needed to bring our research from bench to bedside.
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