Targeting the NAPE-PLD Pathway for Treatment of Pressure Ulcers
Abstract
Our proposed studies address the Fiscal Year 2022 (FY22) Peer Reviewed Medical Research Program (PRMRP) Internal Medicine Topic Area of Pressure Ulcers and the FY22 PRMRP Strategic Goals of Treatment – Develop and test therapeutics or dressings that enhance wound healing, as well as Foundational Studies – Improve understanding of long-term complications and comorbidities of associated diseases and conditions. Pressure ulcers, also known as bed sores, can rapidly develop when an individual is unable to frequently shift positions to relieve pressure on the skin and underlying tissue when sitting or lying down. Pressure on the skin reduces the amount of blood that reaches the skin, damaging the underlying tissue. Patients that are particularly vulnerable to pressure ulcers include those with injuries that restrict their ability to move (for example, spinal cord injuries and hip fractures) or those with medical conditions that make them less sensitive to skin sensations that normally cause individuals to frequently shift position (for example, individuals with diabetes). Pressure ulcers are especially of concern in the military health care setting because of the increased frequency of immobilizing injuries such a spinal cord injury compared to the civilian population. Military Veterans also have an increased frequency of diabetes compared to the civilian population. While pressure ulcers may be initially mild, they can rapidly worsen to where the top layers of the skin are broken and further progression can lead to exposure of the fat layer beneath the skin and also muscles, tendons, and bones. Not surprisingly, such deep wounds can easily become infected, greatly exacerbating any already existing health conditions. About one-sixth of patients with chronic foot ulcers require amputation, and about one-third of patients with these amputations will still die within 2 years. Despite the potentially dire consequences of skin ulceration, no new therapeutic medications for skin ulcers have been approved by the U.S. Food and Drug Administration (FDA) for more than 20 years. There is therefore a significant need to develop better therapeutic treatments for pressure ulcers. Here, we present a novel and innovative approach for treatment of pressure ulcers. The rationale for our novel approach comes from a recent bioinformatics analysis examining the relationship between genes and various medical conditions. This analysis showed that individuals predicted to have lower levels of a specific protein, called NAPE-PLD, from their genetic data were much more likely to have been diagnosed with pressure ulcers and chronic foot and leg ulcers. NAPE-PLD had not previously been known to have any role in skin ulceration, so an important goal of our study is to test if mice genetically engineered to lack the ability to make NAPE-PLD are more sensitive to developing pressure ulcers than mice with a normal amount of NAPE-PLD. We will also test if mice that lack the ability to make NAPE-PLD take much longer to heal when their skin is wounded than mice that can make NAPE-PLD. If we find that mice lacking NAPE-PLD are indeed more sensitive to developing pressure ulcers and that their wounds take longer to heal, this result would support the need to study how NAPE-PLD protects the skin and helps wounds to heal. Such studies could also help us understand how diabetes worsens pressure ulcers because there is evidence that diabetes decreases the levels of NAPE-PLD is some tissues, although this has not been examined in the skin or in the immune cells that might be important for the development of pressure ulcers. We have previously studied NAPE-PLD and have recently identified some drug-like chemicals that make the protein work better (NAPE-PLD activators) at least in the test tube and with isolated cells. NAPE-PLD in the body makes a fat-like molecule called palmitoylethanolamide (PEA), and PEA has previously been shown to have certain effects on im
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310064
Entities
People
- Sean Davies
Organizations
- United States Army
- Vanderbilt University