Project Three: New drug discovery for inhibition of inflammation and fibrosis

This project is focused on the development and validation of noninvasive biomarkers to characterize disease progression in Duchenne Muscular Dystrophy (DMD), Collagen VI related myopathies (Ullrich and Bethlem) and the Dysferlinopathies (LGMD2B/MM). Despite the poor prognosis of muscular dystrophy, therapeutic interventions have been lacking and outcome measures for clinical trials have been limited to measures of muscle function and quality of life, serum biomarkers of muscle breakdown, and invasive muscle biopsies. Additional quantitative outcome measures that are noninvasive and sensitive to changes in muscle structure and composition are needed to facilitate the rapid translation of promising new interventions from preclinical studies to clinical trials. Therefore, Project 3 is focused on magnetic resonance imaging (MRI) and spectroscopy (MRS) strategies to monitor pathophysiological features of dystrophy. In Aim 1 a longitudinal MR natural history study will be implemented to evaluate the progressive involvement of the lower extremity muscles in three distinct muscular dystrophy populations. In addition, this aim will assess the relationship between alterations in MR parameters and loss of muscle strength and function. Aim 2 is an exploratory aim that focuses on the development of novel MR strategies to quantify fibrosis in dystrophic skeletal muscle. State-of-the art sequences, such as ultra short echo and spectroscopic imaging, will be optimized and tested in murine models of muscular dystrophy in Aim 2a. Aim 2b will rely on the development of a newly designed coil and optimized pulse sequences to quantitatively map muscle fibrosis and intramuscular fat in subjects with muscular dystrophy using a clinical 3T system. Finally, a combination of cardiac MR techniques will be implemented to evaluate cardiac function and progressive myocardial involvement in boys with DMD. We anticipate that the MR techniques optimized and validated in these studies will be appropriate for clinical trials in a wide range of muscular dystrophies.