The Role of Calcium and Redox Signaling Complexes in Duchenne Muscular Dystrophy
Abstract
Scientific Objective and Rationale: Inherited myopathies, such as Duchenne Muscular Dystrophy (DMD), have a common fault in the muscle. This common fault or problem is a calcium channel inside the muscle that is too leaky to calcium. This is a problem as normal muscle function is regulated by tightly controlled changes in calcium levels following the signal from the nerve to contract. A leaky calcium channel can also be a result of the influence of reactive oxygen species (ROS), which can promote damage and inflammation in the muscle. What is needed is an understanding of what is a healthy leak of this calcium channel, what is the leak in a diseased leaky calcium channel, and what downstream effect ROS has on a calcium channel. These studies need to be performed in adult skeletal muscle from the mouse model of DMD, not in cultured cells, to be able to best extrapolate what is occurring in DMD patients. The Principal Investigator (PI) has developed a new single muscle fiber fluorescence-based method that is sensitive enough to measure and characterize the calcium channel leak in dystrophic muscle. This platform also provides the opportunity to investigate if calcium and ROS influence each other. The PI will also utilize a Food and Drug Administration (FDA)-approved drug that has been used to treat cancer that is able to inhibit the production of a ROS implicated in DMD progression. Previously, antioxidants have been used to reduce the ROS in dystrophy, but these have been found to have little therapeutic value. Therefore, a better description of how ROS is produced and the effects on calcium could highlight new therapeutic targets for the treatment of DMD pathology. Focus Area: Clinical studies, novel interventions, and drug and biologic delivery technologies designed to improve clinical care and quality of life - skeletal muscle. PI’s Career Goals: The PI is committed to attaining an independent career in Duchenne research, with the goal of finding an intervention that can help both newly diagnosed DMD patients and those that are further in the disease progression. This award will allow the PI the time and mentorship to perform highly novel research with the hope of identifying new targets for drug development. The research and career development plan under this award will allow the PI to fully develop the skills required to function as an independent scientist and move towards research that will be more applicable to the clinic. Ultimate Applicability of the Research: One aim of proposed research is to repurpose an existing FDA-approved drug that targets ROS and see if it can alleviate pathology and calcium dysregulation in both early and more progressed DMD patients. Preliminary data utilizing this drug have been promising, with improvement in muscle strength in the mdx mouse model of DMD and a resistance to contraction-induced damage. The ROS species this drug targets is also important in immune cell function; this presents one potential risk that can be identified this early, which is suppression of the immune system. This can also occur with the use of prednisone, which is conventionally used in the treatment of DMD. Predicting the time it may take to achieve a patient-related outcome is difficult; however, positive results from this study and the fact that this drug has already been through safety testing in humans for cancer trials would mean that this drug could be tested in human DMD clinical trials much faster. This work will help to advance the field of Duchenne research by seeking to understand how critical processes involving calcium and ROS affect each other and lead to hallmarks of the muscle disease. By testing a drug already approved by the FDA that has already shown encouraging results, this work can also further establish important pieces in such a multifaceted and elusive disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810302
Entities
People
- Tanya Cully
Organizations
- Baylor College of Medicine
- United States Army