Bioactive Sphingolipids and Wound Healing
Abstract
Topic Area: Diabetes Difficult to heal wounds are of significant health concern for military personnel and their families, especially those linked to diabetes, since diabetes has reached epidemic proportions in Western society. Despite being linked to high mortality, low quality of life, and other health complications, wounds that are difficult to heal are still a mystery, and most pharmacologic regimens are ineffective. The standard treatment for wounds that are difficult to heal is really expensive and poses limitation to the quality of life of the patient. Currently, the standard of care may involve constant infection control via antibiotics, mechanical off-loading and limb elevation to improve venous blood flow, constant wound dressing, or skin engraftment. Persistent wounds may pose the risk of limb amputation. One of the reasons for the lack of effective treatments is that the mechanisms leading to the development of chronic wounds during diabetes are not well known. The lack of clear understanding in regard to what exactly leads to chronic wound in diabetic patients precludes the development of treatment that could directly target the underlying cause and thus cure the pathology. In this proposal, we hypothesize that a particular protein that exhibits regulatory function and determines the extent of inflammation and proliferation at the wound site is defective during diabetes and thus these defects contribute to the onset of chronic wounds. Thus, this protein, called lysosomal sphingomyelinase, can be targeted pharmaceutically to correct the deficiency. The protein produces several lipid metabolites that have regulatory properties. One of these metabolites is named ceramide, and it regulates the production of agents that regulate inflammation, and the other one is named sphingosine-1-phosphate, and it regulates proliferative responses and the formation of new blood vessels at the site of the wound. All of these processes are either upregulated (inflammation) or downregulated (proliferation and vessel formation) during diabetes and are responsible for the delayed wound healing. The studies in this proposal are aimed at testing directly the role of ceramide and sphingosine-1-phosphate in the wound healing process using mice. In our first aim, we will use a genetic approach to generate mice with low production of ceramide and sphingosine-1-phosphate by deleting the lysosomal sphingomyelinase in macrophages via bone-marrow replacement strategy. Then, we will test whether these mice have delayed wound healing. Alternatively, we will also use a mouse model of type II diabetes. These mice already have problems with wound healing. In these mice, we will test whether topical application of lysosomal sphingomyelinase and its product will improve the healing process. Overall, these experiments will show whether the sphingomyelinase, ceramide, and sphingosine-1-phosphate are likely therapeutic tools to help the wound healing process in diabetic patients. The second aim is focused on identifying a biomarker for delayed wound healing that could be measured in the serum of diabetic mice. The premise for this is based on observations that the loss of lysosomal sphingomyelinase that occurred during diabetes is accounted by an increased secretion of an alternative form of the protein, produced by the same precursor in the macrophages at the site of the wound. We will test whether the activity of this secretory form can be measured in serum of mice and whether it correlates with the rate of wound healing and/or the onset of diabetes. If indeed we discover such correlation, then we can propose that the secretory activity will be an excellent candidate for biomarker that would predict the propensity to chronic wounds. In addition, because it indicates what the specific defect is at the wound site, it will guide physicians to appropriate treatment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610384
Entities
People
- Mariana Nikolova-karakashian
Organizations
- United States Army
- University of Kentucky