Exploiting the Paracrinelike Effect of Prohibitin-1 to Treat Septic Cardiomyopathy
Abstract
Septic shock is a very serious, often fatal clinical condition resulting from an infection or tissue damage. In response to the infection or damage, the immune system becomes over-stimulated and this leads to a hyper-inflammatory stress throughout the body. This stress causes organ systems in the body to fail, particularly the heart. This clinical condition, called septic cardiomyopathy (SepCM), is a major cause of death. Almost one million people in the U.S. have sepsis each year, and 30% die from it. SepCM does not discriminate, it affects young and old alike, including Armed Forces personnel. A report released last year by the U.S. Armed Forces Medical Examiner showed that heart failure was the cause of more than half of all infection-related deaths in U.S. military personnel from 1998-2013. This proposal, to address the Peer Reviewed Medical Research Program topic area of ?Cardiomyopathy,? contains a description of experiments that we believe will lead to a treatment that will stop SepCM, and perhaps even save the lives of patients experiencing septic shock. The idea behind this proposal stems from our lab?s exciting recent findings that a common protein found in every cell of our bodies may be acting as a ?brake? on inflammation during sepsis. In other words, this protein may be working in our bodies to try to restore normal organ function during sepsis by blunting the hyper-inflammatory stress coming from our immune system. What we observed is that we can inject this protein into mice experiencing septic shock and completely restore normal heart function, thereby rescuing the mice from death. Therefore, we are proposing to use this protein as a ?blueprint? to design a new drug for SepCM based on this protein?s normal function during sepsis. In the first set of experiments, we will work to establish the optimal dose (i.e., amount) of this protein necessary for its therapeutic effect in septic shock. We will also establish the timeframe during sepsis that is most effective for this protein to work. To do this, we will use experimental models of septic shock in human heart cells and in mice. In the second set of experiments, we will work to identify which parts of this protein are necessary for its therapeutic effect, since whole proteins do not make ideal drugs due to their size and chemical structure. These experiments will involve molecular biology and bio-engineering approaches in bacterial systems and cell cultures. If fragments of the protein are found to have therapeutic effect, these will be further tested in our cell and mouse models of septic shock. The work outlined in this proposal is innovative and cutting-edge. Most importantly, it is expected to positively impact Armed Forces personnel and the general public for the following reasons: (1) It will lay the groundwork towards development of a drug to protect the heart and other vital organs during septic shock. (2) It will provide critical information for other researchers and clinicians in their search for new treatments for septic shock. (3) It will generate new scientific information about this protein?s role in regulating inflammation, which would be useful for development of new therapies for many other diseases.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910037
Entities
People
- Ethan Anderson
Organizations
- United States Army
- University of Iowa