McLaughlin, Patricia J., PhD
Reversal of complications in wound healing in type I diabetes by topical treatment with naltrexone
General Research Subject: Type 1 Diabetes
Focus: Complications\Hypoglycemia, Foot Care\Lower Extremities
Type of Grant: Basic Science
Project Start Date: July 1, 2009
Project End Date: June 30, 2012
Complications in wound healing are a high risk associated with diabetes. If untreated, they can lead to systemic infection, pain, ulceration, and amputation, and may even be fatal. Wound healing occurs through regulated processes that are dependent on cell proliferation. Innovative ideas that employ new approaches and agents to bridge basic science and translational research are needed. This grant proposal meets this challenge by proposing a new topical treatment for wound healing that enhances cell replication and reduces complications associated with diabetes.
Our laboratory discovered a biological axis consisting of the opioid growth factor (OGF)-OGF receptor (OGFr) axis, that forms an inhibitory pathway regulating cell proliferation in epithelium. Blockade of the OGF-OGFr pathway using naltrexone (NTX), an opioid antagonist, markedly enhances cell proliferation and promotes rapid closure of corneal wounds. We have compelling evidence that topical application of NTX also enhances closure of full-thickness wounds in diabetic animals.
The long-range goal of this research is to understand the pathophysiological mechanisms associated with complications of diabetes (delayed wound healing). Using a model of full-thickness cutaneous wounds in adult male rats that are rendered Type 1 diabetic, topical application of NTX will be studied for its efficacy, toxicity, and mechanism of action. We are particularly well-prepared to undertake the proposed research because the principal investigator has the knowledge, resources, and reagents required for completion of the studies. The proposed work is innovative because it focuses on modulating a native biological pathway in order to accelerate wound repair, and reduce diabetes associated complications.
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 targets one of the major complications associated with Type 1 or Type 2 diabetes, specifically problems and/or delays in epithelial wound healing. Our research focuses on the discovery that endogenous opioids and their receptors, present in skin, regulate the course of homeostasis and renewal of epithelium by serving as a tonically regulated inhibitory system. This pathway is the opioid growth factor (OGF) - OGF receptor (OGFr) axis, and it functions in both normal and neoplastic tissues. OGF is present in very high levels in diabetes, and may contribute to the prolonged closure of wounds characteristic of the disease. Blockade of the tonic interactions between OGF and OGFr results in up-regulation of cell replication and accelerated re-epithelialization.
Using an opioid receptor antagonist naltrexone to block these pathways in a rat model, the pathophysiology and mechanisms related to wound closure can be studied. The long-range goal of this research is to develop a safe and effective compound that accelerates wound closure and reduces wound-related infections. The objective of this research will be to study the role of the OGF-OGFr axis in wound closure and to develop a treatment using naltrexone that is efficacious, non-irritating, and easily applied, thus reversing complications of wound healing associated with diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Complications in skin wound healing are common in diabetes and if left untreated, may lead to systemic infection and even amputation. Current therapies do not target the biological processes that cause these complications, and current ointments are not completely effective. The objective of this research proposal is to understand the pathophysiology of delayed wound closure in diabetes and to identify the pathways associated with re-epithelialization. This knowledge will assist in the development of effective therapies to reduce complications associated with wound repair and to prevent infections associated with delays in closure and/or recurrent wounds.
Utilizing the active compound naltrexone that is an antagonist to the pathway involved in re-epithelialization, a topical formulation that is efficacious, non-irritating, easily applied, and economical will be investigated in order to establish a therapy that accelerates closure of surface wounds.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
As a cell and molecular biologist, I have worked on understanding the role of the Opioid Growth Factor (chemically termed methionine enkephalin) and its receptor OGFr in normal and neoplastic cells. Specifically, with my scientific colleagues I have spent several years on the isolation, identification, and molecular characterization (i.e., cloning and sequencing) of OGFr in mouse, rat, and human. To bring this knowledge full circle and be able to focus on translational medical research that uses the OGF-OGFr to ameliorate health risks is quite gratifying.
With the insight that diabetes is associated with elevated levels of OGF, and knowledge of ways to block the pathways targeted by OGF, I am particularly excited to explore the imbalance of the OGF-OGFr axis in diabetes. The award will enable me to continue the research focusing on a treatment for a major complication related to wound healing. The impact of this treatment will not only touch the lives of those with diabetes, but impact normal individuals.
In what direction do you see the future of diabetes research going?
I see the future of diabetes research taking a two-pronged approach to addressing the clinical problem. With the catastrophic increase in diabetes both in the US and worldwide, complications associated with this disease will be more prevalent and therapies will be more urgently needed. One group of researchers will focus research on basic pathways involved in the disease. Other investigators, of whom I am one, will aggressively be involved in translational research, attempting to apply knowledge learned in drug discovery and animal models to the clinical arena. Together we should be able to make significant inroads into understanding the etiology, pathogenesis, and treatment of diabetes, giving these patients the highest quality of life possible.
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