Zhang, Sarah Xin
Molecular mechanisms for diabetic retinopathy
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Complications\Ocular, Other, Signal Transduction (Non-Insulin Action)\Cytokines and Apoptosis
Type of Grant: Basic Science
Project Start Date: July 1, 2011
Project End Date: June 30, 2014
Cell death in retinal endothelium (the inner lining of blood vessels) occurs frequently in the diabetic patients. The consequence of this event is insufficient blood supply to the retinal neuron (ischemia), which results in an over-production of growth factors, leading to uncontrolled blood vessel growth. These newly formed blood vessels have defective structure and are leaky, resulting in bleeding and swelling of the retina (edema), eventually leading to vision loss. Therefore, protecting retinal endothelial cells from the early damage and cell death could prevent the vision disability in diabetic patients. In this application, we propose to delineate a novel mechanism of retinal endothelial cell death induced by diabetes and identify the key molecules that mediate the apoptotic process of retinal endothelial cells. We will also evaluate the therapeutic effect of a novel gene therapy targeting this pathogenic gene on inhibiting retinal vascular leakage and vascular cell death in diabetic animals. We believe that these important studies will provide new insight into the mechanisms by which diabetes causes vascular damage in the eye and reveal new therapeutic target for the prevention and/or treatment of this debilitating affliction.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The project focuses on the molecular mechanisms that diabetes causes damage to vascular endothelial cells in the retina (a thin layer of neural tissues in the back of the eye), which is also known as diabetic retinopathy. Diabetic retinopathy is a common complication of diabetes and a leading cause of blindness in the working-age population. Diabetic retinopathy affects both type 1 and type 2 diabetics, and it occurs more frequently in patients with longer duration of diabetes. Although well-controlled blood glucose level and traditional therapies, such as laser photocoagulation, can reduce the risk of severe vision loss in diabetic patients to some extent, currently there is no effective therapy in preventing and treating this sight-threatening condition. This is largely due to the lack of knowledge how diabetes affects retinal vascular cells, and how these cells lose their function and die in the diabetic state. The current project focuses on elucidating a novel pathogenic gene that mediates diabetes-induced cell death in vascular endothelial cells, promoting retinal blood vessel dropout, ischemia of retinal tissue, and eventually abnormal new vessel growth. Using the state-of-the-art new technology, we will generate a conditional knockout mouse model that lacks this gene specifically in vascular endothelial cells. Using this model, we will dissect how this gene regulates signaling pathways that control endothelial cell survival and whether targeting this gene would be a promising therapy in rescuing endothelial cells and vascular function in the diabetic condition. Therefore, the outcome of this project will provide critical information for understanding how diabetes causes damage to the blood vessels in the eye, which may lead to ultimate vision loss, and help in developing new drugs targeting key genes that cause the disease.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Diabetic retinopathy is a common complication of diabetes, leading to severe vision impairment, and causing profound effects on work disability and reduced quality of life in diabetic patients. The effective therapies for preventing and treating this devastating complication are currently lacking. A critical barrier is the unknown mechanism how diabetes causes damage to the retina, a tissue that generates and sends visual signals to the brain. This project addresses this fundamental question by elucidating the role of a novel pathogenic gene in retinal endothelial cell death during diabetes. We anticipate that the outcome of this project will provide important information that helps understanding how retinal cell die in the diabetic state. We are also expecting identifying a new target for developing drugs to prevent and treat this disease.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have been involved in diabetes research for over fifteen years. Trained as an Ophthalmologist and a retinal specialist, I have encountered numerous patients with diabetic retinopathy, a devastating disease that causes vision loss in adults. In contrast to the increasing diabetic retinopathy rate due to the rising epidemic of diabetes, very limited reliable therapies are available for treating this disease. I believe that developing new effective therapies for diabetic retinopathy is urgently needed, and that understanding the molecular mechanisms how diabetes causes damage to retinal cells, and, thus, identifying critical genes that mediate the damage is the key for developing new drugs. This award will enable us to address these foremost important questions: 1) understand the mechanisms of diabetic retinopathy; 2) discover a novel pathogenic gene of diabetes-induced vascular damage. We anticipate that this project will generate important information that helps us to seek novel and effective ways to prevent and treat diabetic retinopathy.
In what direction do you see the future of diabetes research going?
Diabetes is a systemic disease that affects multiple organs in the body. While tight blood glucose control is important for reducing the incidence of diabetic tissue injury, a large number of diabetic patients are still suffering from various complications including diabetic retinopathy. Therefore, vigorous basic research is very important to elucidate the underlying mechanisms that cause damage to the eye, kidney and peripheral nerves, as well as the cardiovascular system, and to develop new drugs that protect the susceptible tissues against diabetic damage. In addition, clinical research identifying patients at high risk for developing complications and establishing new biomarkers that enables early detection of complications would be equally important in preventing the development of devastating diabetic complications, such as vision loss and renal failure.
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