Chi, Yuling , Ph.D.
Inhibition of prostaglandin transporter accelerates wound healing in diabetes by promoting angiogenesis
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications, Complications\Macrovascular-Cellular Mechanisms of Atherogenesis in Diabetes
Type of Grant: Junior Faculty
Project Start Date: January 1, 2011
Project End Date: December 31, 2013
Funded by The Fineberg Foundation
Diabetic foot ulcer (DFU) is one of the most feared complications of diabetes. The lifetime risk of a person with diabetes developing foot ulceration is reported to be as high as 25%. Due to lack of effective treatment, this condition has a high frequency of recurrence, and consequently leads to amputation. It is estimated that more than a million people with diabetes require limb amputation each year, suggesting that one major amputation is performed worldwide every 30 second. The personal, social, medical and economic costs associated with DFU has drastically increased as the world facing an epidemic of diabetes.
The peripheral organs, such as foot, of diabetic patients get injured more often than those of normal individuals because their sensation to noxious stimuli is diminished. Once they are injured, their wounds do not heal easily because their immune response in peripheral tissues is weakened and their cutaneous/subcutaneous endothelium is dysfunctional, which are caused by hyperglycemia and associated with impaired angiogenesis and peripheral ischemia.
Our work has identified a novel approach to sensitize sensory neurons, induce vasodilation and increase blood flow, and stimulate cell growth, by potentiating and amplifying a potent endogenous signaling pathway. We have developed potent inhibitor of the transporter of prostaglandins (PGT) and obtained preliminary data compelling showing that this small compound accelerates wound healing. We propose to further develop proof of concept evidence that PGT is a novel and druggable therapeutic target for the treatment of diabetic wounds.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Our project covers diabetes complications, specifically diabetic neuropathy and diabetic foot ulcer. Diabetic foot ulcer (DFU) is one of the most feared complications of diabetes. This condition has a high frequency of recurrence, and often leads to amputation. Worldwide, it is estimated that more than one million people with diabetes require limb amputation each year, suggesting that one major amputation is performed every 30 seconds. In the United States approximately 15 to 20 percent of 20 million persons with diabetes mellitus will be hospitalized with a foot complication at some time during the course of their disease. One in five infected foot ulcers requires amputation. The economic burden that diabetes and its related complications have placed on the U.S. healthcare system is now estimated to be about $174 billion each year. In spite of widespread incidence and severe consequences, there is no highly effective therapy for DFU treatment.
Our project seeks to understand the role of prostaglandins (PGs) and prostaglandin transporter (PGT) in neuron sensation, blood flow, perfusion to distal limbs and tissues, and blood vessel formation and growth, which are important in wound occurring and wound healing. This research will provide proof of concept evidence that PGT is a novel therapeutic target for wound healing in diabetes and that PGT inhibitors have potential to be developed into drugs to enhance wound healing and reduce the number of limb amputations, and thereby improve diabetic patients' life style and overall well being, and reduce the financial burden that this condition has placed on our healthcare system.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Diabetes is a high risk factor for ulcer development. In addition, diabetes predisposes diabetic patients to be vulnerable to injury mainly because the patients' sensation to noxious stimuli is diminished. Once injured, their wounds do not heal easily due to peripheral ischemia and impaired vessel formation.
Prostaglandins (PGs) are molecules that trigger signals in major tissues and cells throughout the body including the nervous system, connective tissue, skin, and blood vessels. When prostaglandins interact with their receptors (in the same cell or in nearby cells), these naturally occurring chemicals activate responses such as pain, inflammation, blood vessel dilation and formation, and cell growth. Sensation to pain increases the awareness of noxious stimuli and reduces the chance for patients to get injured. Inflammation is essential for initiation of the healing process. Dilation of blood vessels increases blood flow to the wound sites where nutrients are needed for healing. Newly formed vessels provide a platform for blood flow. Therefore prostaglandins are beneficial for wound healing. However most of the prostaglandins are metabolized within 3-5 minutes. Furthermore, their levels are reduced in diabetes, partially due to enhanced degradation/metabolism.
We have been working on prostaglandins transporter (PGT), which controls PG degradation. Genetic deletion or chemical inhibition of PGT raises PG levels systemically in the blood stream and locally in cutaneous wounds. We have developed a potent inhibitor of PGT. Our preliminary data show that topical application of PGT inhibitor accelerates wound healing in mice. Intravenously injected PGT inhibitor increases blood flow to hind limb of rats. These data are compelling and promising. We aim to further advance this project and take it to the clinical stage. We have hope that these compounds can be developed into drugs for DFU treatment.
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 witnessed the detrimental effects of diabetes, particularly DFU. My uncle had diabetes. Seven years after he was diagnosed with diabetes, he started feeling numbness in his feet. One day he bumped into a road curb and injured his left foot heel. The wound couldn't heal and got bigger. His foot became swelling and pus started appearing and spreading. More and more surrounding skin was infected. He tried several antibiotic ointments, wore special shoes to reduce the burden on foot. Nothing seemed to work. Eventually he had to make a tough decision, having his left foot amputated. Thereafter, he lost normal mobility. His life style and overall physiological and psychological conditions were drastically and adversely affected.
Having witnessed the whole process, I told myself that, as a medical research scientist, I must do something. Luckily, I have been working on PGT that regulates important biological signaling and physiological events that are involved in wound healing. I have developed a potent inhibitor of PGT that accelerates wound healing and has great potential to be developed into a drug to treat DFU. This award will enable me to carry on my research and continue my road trip to obtain that effective drug. Without it, the future of this project would be uncertain, delayed at best and stopped at worst, as my current funding is going to end soon.
As for my scientific career, this award will permit me to continue my current research and extend it to future goals. Following receipt of this grant, I will be able to successfully compete for independent NIH funding. The success of my scientific research will allow me to stay on my tenure track, to progress my career, and to find a cure for DFU.
In what direction do you see the future of diabetes research going?
One direction of diabetes research is to understand the fundamental causes of diabetes. Better prevention, treatment, and cure of a disease come after better understanding the causes of the disease. There are two types of diabetes, type 1 and type 2. Type 1 diabetes is caused by a severe lack of insulin. Providing patients with insulin can control the progression of this type of diabetes to a large extent. The more common type of diabetes is type 2 diabetes, which accounts for 80% of cases. Unfortunately the exact causes of type 2 diabetes are not completely understood, although a number of risk factors have been identified. Due to lack of fundamental understanding of type 2 diabetes, the currently available medications are limited to reducing glucose production, or increasing insulin secretion. Better understanding insulin resistance and alternative mechanisms mediating glucose uptake and disposal would provide insights to better design medicines to reduce glucose by increasing insulin sensitivity and/or modulating alternative pathways.
Another direction is to develop effective therapeutics for diabetic complications. In many cases, regardless of how hard the patients and doctors are trying to control blood sugar, diabetes inevitably progresses and eventually leads to serious complications including problems with eyes, kidneys, nerves, heart, blood vessels, and other areas in the body. Currently there is a lack of medicine specifically targeting diabetes caused hypertension, nephropathy, retinopathy, and foot ulcer. Two main approaches (biological and chemical) have been taken to develop therapeutics. Some therapeutics developed by the biological approach, such as stem cell transplantation and tissue engineering, are promising. However, a tissue or cell based approach comes with greater complexity to the solution, since the cells or tissues are expensive to grow and maintain, have a limited shelf life, and are not portable. The chemical drugs are more convenient. Yet, the success rate of finding an effective drug is low. It's often disappointing that one cannot fish out a good lead compound from screening a million synthetic compounds. An alternative method is to identify natural compounds. Nature is a rich source of medicine waiting for us to discover. Lots of leads from layman's use often point to the right direction and can aid us to find effective drugs with lower cost and higher successful rate. Among hundreds of drugs, aspirin, from the bark of willow trees, is still one of the most widely used medications in the world, with an estimated 40,000 tons of it being consumed each year.
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