Targeting SHP2 to Improve Outcome of Duchenne Muscular Dystrophy-Associated Cardiomyopathy
Abstract
In Duchenne muscular dystrophy (DMD), the lack of dystrophin protein leads not only to severe progressive skeletal muscle disease, but also affects the heart muscle. This can lead to heart failure in adult DMD patients. As multidisciplinary therapeutic advances have extended the life span of DMD patients, heart failure has become a major concern. Therefore, new heart failure treatments that are specifically suited for DMD patients are urgently needed. Based on pilot data, we propose that targeting the protein Src homology region 2 domain-containing phosphatase-2 (SHP2) in the heart can substantially increase the resilience of the heart muscle cells in DMD. SHP2’s main function is to regulate protein-based signals in the heart, some of which are known to be highly protective. Whether SHP2 plays a role in DMD-associated heart failure has not been studied yet. The goal of this project is to evaluate whether targeting SHP2 can improve heart function in mouse models of DMD. We will conduct proof-of-principle experiments using either genetic modification to shut off SHP2 or new drugs that have been shown to block SHP2 in laboratory studies. In addition, we will thoroughly investigate which signals are regulated by SHP2 in the heart to better understand how and why blocking SHP2 is protective. This will advance the field of DMD research and will provide new insights that could be applicable not just to DMD, but other forms of heart failure as well. Drugs that can block SHP2 are already in clinical trials for other diseases; therefore, such new medications are likely to become available in the near future. The studies proposed in this application will be a critical first step to establish that SHP2 is a valid new target in DMD-associated heart failure. This would build a solid foundation for future clinical trials in DMD patients. We expect that such new medications would benefit all DMD patients, either preventing heart failure or slowing down heart failure progression. We anticipate that a new treatment that blocks SHP2 would work together with all other treatment approaches that are currently available and could enhance the success of other new therapies aiming to restore dystrophin in the heart muscle.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310711
Entities
People
- Maike Krenz
Organizations
- Curators of the University of Missouri
- United States Army