Pharmacological Regulation of Mechanosensing Signaling in DMD
Abstract
Scientific Objective and Rationale: Duchenne Muscular Dystrophy (DMD) is among the most common lethal muscle diseases in boys, with progressive muscle deterioration. The defect responsible for this disease is an error (called mutation) within the heritable DNA material (gene) that produces the Dystrophin protein. Dystrophin is part of a group of proteins (a protein complex) that work together to strengthen healthy muscles and protect them from injury during contraction and relaxation. In healthy muscles, if there is a tissue tearing or injury, muscle stem cells (MuSCs) are awakened and transition from a silent or quiescent state toward an activated state. This transition is necessary for building new tissue (a process called regeneration). In DMD patients, where muscles are not able to produce a working Dystrophin, the protein complex becomes fragile and every time the muscle contracts, it breaks down. And while the stem cells attempt to build new muscle, before regeneration is complete, there is another round of damage due to the continuous contraction of the compromised dystrophic muscle. Thus, in DMD, repetitive muscle damage elicits a constant need for regeneration and the continuous cycles of muscle damage/restoration eventually exhaust the restless dystrophic MuSCs. Our lab previously showed that, although DMD is initiated by a dystrophin defect, it eventually develops into a stem cell disease. Yet current therapeutic strategies do not take stem cells into consideration. We recently made two striking observations that serve as the rationale of the work proposed here: (1) we discovered that the transition of MuSCs from a quiescent towards an active state is regulated by a molecule called Piezo1, and (2) we found that dystrophic MuSCs have low levels of Piezo1. The objective of this proposal is to pharmacologically treat dystrophic muscles with a compound capable of reactivating Piezo1. We predict that under these treatment conditions, dystrophic stem cells will properly transition toward an active state, leading to enhancement of muscle restoration and activity (function) in DMD. Applicability of Research 1. Types of patients and how this research will help: Current attempts to correct the errors of the dystrophic gene do not target stem cells efficiently. Moreover, not all DMD patients carry the same dystrophin mutation. In fact, scientists have recorded over 7,000 dystrophin mutations, making gene correction a challenging generalized therapy for all patients. On the other hand, transferring healthy stem cells to a site where tissue is damaged, a procedure called cell transplantation, is a daunting therapeutic strategy for muscle diseases due to massive number of muscles in the human body. In the meantime, administration of corticosteroids (strong anti-inflammatory drugs) is the current standard of care for DMD, which is only supportive and often associated with undesirable side effects. An alternative therapeutic possibility would be to minimize stem cell exhaustion, maintain and boost their ability to regenerate muscles. We recently discovered that the molecule Piezo1 is important for stem cell regulation, but it is produced at low levels in dystrophic compared to healthy MuSCs. In this proposal, we will test the potential of a drug that elevates Piezo1 actions to increase the regeneration abilities of dystrophic MuSCs. Such therapeutic intervention will help all dystrophic patients, independently of which dystrophic mutation they carry. 2. Potential clinical applications, benefits, and risks: The scientific discoveries we made in our laboratory, could be transformed into a new treatment and approach to medical care that has the potential to improve the health of the dystrophic population. The therapeutic intervention to be tested here relies on enhancing the endogenous ability of stem cells to restore muscles and can be used alone or in combination with other therapies . Moreove
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211116
Entities
People
- Foteini Mourkioti
Organizations
- United States Army
- University of Pennsylvania