Extracellular Vesicles as Biomarkers, Mediators of Immune Dysfunction, and Universal Countermeasures Against Radiation Syndrome and Associated Polytrauma
Abstract
What Is the Problem: Radiological and nuclear threats are increasing rapidly. Examples can include detonation of a nuclear weapon, use of a dirty bomb, a stealth radiological dispersal device, deliberate attack on a nuclear power plant, and radiological/nuclear accidents. The number of people who will need medical attention after a large-scale event will be large. These threats have the ability to involve military and civilian populations. Radiation causes significant death as a result of tissue damage, with the degree of damage depending on the duration and dose. Radiation survivors have a significantly dysfunctional immune response causing damage to the victim’s own tissue yet unable to control infection. In addition, when radiation injury is accompanied by additional traumas, such as burn injury, there is increased chance of acute death and even more altered effects on the immune system. After radiation injury and combined injuries, patients experience a range of short and long-term consequences such as increased rates of infection, cancer and many other diseases. To add to this, if you consider that at times it is not immediately obvious that people have been exposed to radiation, for example placement of a stealth radiological source in a public area or water source, we currently have no way to rapidly identify individuals exposed and the magnitude of exposure. Our Solutions: Our group has spent 25 years investigating ways to explain and solve these problems, developing models of burn injury, radiation injury and combined injury models in clinically relevant mouse models. We also correlate all our findings in trauma patient samples, having developed a pipeline to collect immune cells from burn patients. We base this proposal on three key findings: 1. We have discovered that naturally occurring lipid-protein structures, called extracellular vesicles (EV), normally produced by cells as a means for cells to signal to each other, become bad and now able to cause the dysfunctional immune response associated with radiation and burn injuries. We believe that using a simple naturally-occurring molecule isolated from milk called lactadherin, we can deplete these EV from a patient and help return the immune system to normal. 2. In addition, we have shown that we can examine the specific cargo of the EV and the identity of the cargo can be used as a stable biomarker to detect and quantify radiation exposure in people. We can examine EV from blood or saliva of patients which allows us to examine large numbers of people quickly. Development of this biomarker and the calculations to relate EV cargo with degree of exposure is the first step to developing a point-of-care device that can be used in the field. 3. We have also discovered that EV produced by certain stem cells (MS-EV) cultured in the laboratory injected into radiation and/or burn injured mice prevented these mice from forming a dysfunctional immune responses. These MS-EV can be grown in large quantities, stored for very long periods of time (even at 4 degrees C refrigerator temperature), and can be used universally without having to be tissue-matched with recipients. We will test these ideas using our pre-clinical mouse models of injury, and with human samples collected from burn patients, as detailed in the Proposal. Benefits: We propose that the main benefits of this study are that twofold: (1) EVs can be used early and non-invasively to detect and quantify radiation exposure and (2) removal of host pathogenic EV or administration of MSC-EV early and late after radiation injury or complex burn + radiation injuries will diminish dysfunctional immune responses and will, in turn, improve short and long-term clinical outcomes and prevent the devastating consequences of these injuries. Our goal is to convert these findings into tangible benefits, as it relates to Service Members and all our patients, to help address their imme
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310913
Entities
People
- Robert Maile
Organizations
- United States Army
- University of Florida