Wagner, Denisa D., PhD
Inhibition of the generation of neutrophil extracellular traps (NETs) may accelerate wound healing in diabetes
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Clinical Therapeutics/New Technology, Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications, Complications, Immunology
Type of Grant: Innovation
Project Start Date: July 1, 2013
Project End Date: June 30, 2015
Diabetes is a global health problem. Patients suffering from diabetes usually have difficulties in wound healing which can lead to serious complications such as amputation. To date, identification of the underlying causes of and effective therapies for these non-healing wounds remains challenging. Neutrophils, white blood cells that provide a first line of defense against infection, were recently found to release their DNA forming "NETs" in order to trap and destroy bacteria. This kind of host defense may do more harm than good for wound repair because the infection fighting also causes highly toxic effects to the host tissue. Preliminary results indicate that neutrophils from diabetic mice make more NETs and inhibition of NET formation accelerates wound healing in healthy mice.
The aim of the study is to understand why neutrophils make more NETs in diabetes and how neutrophils and their extracellular DNA NETs affect wound repair in this condition. Because neutrophils are more active under diabetic conditions, the hypothesis is that these neutrophils release more NETs that worsen wound repair. Therefore, inhibitors targeting the enzyme that promotes NET release may improve wound repair in diabetes. The findings of this project using diabetic mouse models will provide new insights on diabetic neutrophil biology, the role and impact of neutrophils and NETs in diabetes and its associated complications and may open up a new strategy to treat non-healing wounds by inhibiting the release of neutrophils' toxic cell contents.
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 focuses on studying how neutrophil behavior is modified by diabetes and how this alteration impacts complications such as wound healing. Diabetes is a prevalent metabolic disease worldwide. One of the most common diabetic complications is non-healing wounds which in severe cases can result in amputation. In the US alone, ~8.3% of population is diagnosed as diabetic and >60% of non-traumatic lower-limb amputations occur in diabetics due to poor wound repair. Neutrophils are white blood cells that can capture and destroy bacteria by extruding their DNA and cellular contents to form NETs (neutrophil extracellular traps). However, these NETs may also do harm to host tissues that is unfavorable to healing. Our preliminary data on normoglycemic mice show that the absence of an enzyme that mediates generation of NETs facilitates wound repair. Our study now aims at understanding whether and why neutrophils are more primed to produce NETs and whether the hyperactive NET-making neutrophils worsen wound healing under diabetic conditions.
The findings of this project will provide new insights on diabetic neutrophil biology, the role and impact of neutrophils and NETs in diabetes and its associated complications. With a better understanding of diabetic neutrophil behavior, we hope our findings can identify the key player(s) that retard wound healing and thus suggest new alternatives to treat non-healing wounds. Eliminating the undesirable effects from neutrophil-mediated host defense by using a topical inhibitor that can restrict production of NETs to promote wound healing can be an attractive therapeutic option. More importantly, our findings may also lay the ground for further pre-clinical investigation on how exaggerated NETs production impacts diabetic etiology and other complications.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
Identification of the underlying causes of non-healing wounds in diabetes remains challenging. There are to date no effective therapies for treating these non-healing wounds. Our findings will advance knowledge of the role of immune cells in wound repair and we hope will suggest new therapeutic options for wound care in diabetes such as topical application at the wound area of a drug that prevents neutrophils from extruding their toxic chromatin and thus facilitates healing and regeneration.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes is a global health burden that attracts attention from various disciplines to look for novel and more effective treatments and prevention strategies. My laboratory has investigated and discovered the detrimental roles of activated neutrophils and NETs in disease conditions such as deep vein thrombosis, cancer-associated thrombosis, myocardial infarction and transfusion-related acute lung injury. Because neutrophil behavior can be modified by hyperglycemia and diabetic conditions, we are enthusiastic to make a cross-disciplinary effort in expanding our knowledge to diabetic neutrophil biology and how neutrophils/NETs play a role in diabetes development and its complications. This award comes at an excellent time in supporting us to move into an exciting new field of diabetic immunology.
In what direction do you see the future of diabetes research going?
Diabetic immunology is an emerging and important field because diabetes clearly represents a chronic inflammatory condition. What components of the immune system are involved and how they are triggered, altered and participate in the development and progression of diabetes, obesity and metabolic syndromes remain open questions that deserve more investigative efforts.
Although progressing slowly, diabetes research should also become more translational and practical. While novel targets are identified through the cross-disciplinary and collaborative efforts in basic science, more follow-up clinical studies should be encouraged to evaluate whether these findings can offer the diabetic population more effective treatment options in ameliorating diabetic conditions and complications, including wound healing. Eventually, the goals of diabetes research are about preventing the occurrence of diabetes and improving the quality of life of diabetic patients.
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