Longitudinal Analysis of Disease Site Activities Impairing Wound Healing in Epidermolysis Bullosa and Development of Therapeutic Strategies
Abstract
Wound healing is a multi-step process that is needed to close an open wound and repair damaged skin. Several different cell types present in the skin, including various immune cells, are critically important for rapid and complete wound closure. However, under certain conditions, a well-coordinated process of wound healing can be disrupted or impaired, e.g., when unfavorable microbes (bacteria, viruses, fungi) grow in the injured skin. Then, the wound is unable to heal properly and becomes non-healing or chronic. This type of wound develops into chronic ulcers and presents a substantial health threat. Development of chronic wounds is very common for patients affected by hereditary Epidermolysis Bullosa (EB). Separation of skin layers following minor trauma to the skin is a hallmark of the disease. It leads to the development of blisters, erosions, and non-healing wounds, which are associated with numerous complications including infection, sepsis, dehydration, deformities, and cancer. Attending physicians lack convenient and effective treatment options for EB chronic wounds, and surprisingly little is known as to why some wounds heal (albeit at a slower rate) while others persist for long periods of time. Presently, there are no objective measures or markers that can predict the outcome of the wound. Understanding the molecular and cellular dynamics of wound healing, particularly in EB patients, can offer better treatment options for patients and, possibly, help to identify biomarkers predicting wound outcome. Currently, day-to-day management of wounds in EB patients is revolving around judicious use of bandages (wound dressings). We found that cellular and molecular components of the wound can be recovered from these dressings and be a very useful research tool. Having access to patient’s bandages, we already established a noninvasive technique for collection of cellular material from wounds. Data collected using this sampling method correlates very well with data collected by more invasive techniques. To study the interplay between cellular and molecular components of the wound, we propose to conduct cross-sectional and longitudinal studies. Cross-sectional design involves collection of EB samples (bandages) from a number of early, established, and chronic wounds following analysis of the molecular and cellular components by various methods. After completion of these analyses, the proportion of specific cells and molecules in early, established, and chronic wounds will be identified. Comparative analysis of the resultant data between different wound types will define the cellular and molecular signatures of these wounds. In longitudinal studies, sample collection will start at the early stage and continue until the wound is completely healed or becomes chronic. Samples (bandages) will be collected and analyzed once a month for a total 12 months. It is expected that cumulative data will help to identify specific biomarkers defining wound outcome. Microbial pathogens play an important role in wound healing. Because changes in microbial communities could reflect wound healing, in parallel with the collection of bandages in longitudinal study, the sampling of the wound-colonizing bacteria will be done using swabbing of the wound surface. This is a well-established noninvasive method, which allows the collection of microbes for further analysis of the microbial populations by sequencing of the microbial DNA. Also, using a preclinical animal model recapitulating human EB, two drugs, Ladarixin and TAK-242, will be tested for their ability to improve wound healing by suppressing the recruitment of immune cells, called neutrophils, to the established wounds. Testing of at least two types of drugs on a relevant animal model will create a foundation for clinical trials aimed at treatment of EB patients to reduce and, possibly, eliminate development of chronic wounds. Collectively, identification of the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810628
Entities
People
- Olga Igoucheva
Organizations
- Thomas Jefferson University
- United States Army