This MDCRC is organized around the central theme of improving muscle regeneration in a number of types of muscular dystrophy by inhibiting fibrosis and thus improving muscle repair and limiting fatty replacement of muscle. Interacting and collaborative studies are proposed to address by what mechanisms muscle fibrosis and fat infiltration occur. Existing drugs will be evaluated for the ability to positively impact fibrosis and the resulting pathology in two mouse models of human muscular dystrophy. (The mdx mouse is a model for Duchenne muscular dystrophy and the A/J mouse is a model for LGMD2B/Miyoshi muscular dystrophy.) In addition, we will define new modifiers of fibrosis in the heart in the mouse model of DMD, which could lead to the defining new drug targets. Lastly, we will continue to develop non-invasive (MRI) approaches to monitoring and describing the natural history of disease progression in human muscular dystrophies, with the goal of developing sensitive measures for drug efficacy to aid in clinical trial design and success.
This Wellstone MDCRC was originally formed as a joint center between the University of Pennsylvania and Johns Hopkins and was focused on improving the dystrophic phenotype by modulating muscle growth pathways. The current focus of the center on fibrosis (both in skeletal muscle and in the heart) and regeneration of skeletal muscle necessitated a reorganization of the Center, bringing in the new Co-Director, Elizabeth McNally, and investigators from UCLA. The initial five year funding period of this Center was focused on promoting muscle growth and inhibiting protein breakdown as a means to slow the progression of the muscular dystrophies. Much of the focus (three of the four projects) was on myostatin inhibition. With myostatin inhibitors now in clinical development, as well as others in the drug development pipeline, there is no longer a need for a major effort to define novel targets to achieve myostatin inhibition. MRI imaging of patients (now Project 3) continues as part of the Center, as does our Scientific Research Core (Physiological Assessment Core). As mandated by the MDCRC directives, our Administrative and Training Core has been split into two separate Cores.