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DRC Director's Report - February 2019

The Department of Defense office of the Congressionally Directed Medical Research Programs has awarded DRC member, Ethan Anderson, Associate Professor College of Pharmacy, funding as part of its Peer Reviewed Medical Research Program (PRMRP) Discovery Award competition. The project is: Exploiting the Paracrine-Like Effect of Prohibitin-1 to Treat Septic Cardiomyopathy. The grant will provide $310,000 in total support over a 2-year period.

The project will examine the mitochondrial membrane protein Prohibitin-1 (PHB1) in a model of heart failure that is associated with the often lethal disorder septic shock. Heart failure is associated with impaired cardiac metabolism that limits the energy production that the heart requires for maintaining its contractile function. It is evident that PHB1 may regulate glucose metabolism in the heart, possibly via a unique mechanism in mitochondria. However, the Anderson laboratory has discovered another potential mechanism by which PHB1 could protect the heart.

This application, which was submitted in response to the PRMRP topic area of ‘Cardiomyopathy’ stems from Anderson’s exciting unpublished, preliminary findings where they have identified a previously unknown role for a family of lipid raft-associated proteins, called ‘Prohibitins,’ during sepsis. Sepsis is a very serious, often fatal clinical condition resulting from an infection or tissue damage. Prohibitins (PHB1, 2) are normally found in the plasma membrane and densely packed in mitochondrial membranes, where they are at the nexus of cellular metabolism and life/death signaling pathways. 

The idea behind this proposal stems from the Anderson’s lab’s exciting recent findings that PHB1 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 that is induced by our immune system. The Anderson laboratory has observed is that when PHB1 is injected into mice experiencing septic shock, it completely restores normal heart function and metabolism, thereby rescuing the mice from death. Therefore, Dr. Anderson proposes to use this protein as a ‘blueprint,’ to design a new drug for septic cardiomyopathy (and potentially other inflammatory and metabolic disorders) based on their recent discovery of the protein’s normal function during sepsis.

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