The goal of this BIRT supplement is to develop a set of quantitative MR imaging and spectroscopy tools that correlate with known cellular events to derive surrogate markers that identify muscle inflammation, damage and recovery and to monitor the time course and evolution of these processes - a non-invasive biopsy. The proposed project will be done in dystrophic disease models in dogs and mice. Imaging based on changes in T2 relaxation is currently the clinical standard to identify regions of pathology in muscles and soft tissues. These methods are useful because of their sensitivity to a wide range of mechanisms, but this generality means they are unable to identify specific cellular processes in the affected areas. We recently began studies with Stephen Tapscott's lab to monitor their canine model of dystrophy, and specifically to work out MRI methods to monitor the inflammation and its regression that follows focal injection of AAV-microdystrophin gene constructs in normal and cxmd dogs to distinguish inflammation from the positive effects of gene transfer, and to monitor therapeutic interventions against inflammation using conventional tools. This new project will test 1H, 23Na and 31P imaging and spectroscopy methods (in addition to conventional T2 weighted and STIR imaging) for sensitivity and specificity of the underlying pathologies verified by biopsy in Dr. Tapscott's lab. Related experiments in collaboration with Dr. Jeff Chamberlain's lab will quantify the time course of lesion progression and recovery in leg muscles of normal and knockout mice lacking dystrophin and/or utrophin by microinjections of bipivacaine into the tibialis anterior, quadriceps and triceps surae using the same MRI and MRS methods. Histological examinations and immuno-histochemistry of the identified and imaged regions will validate the cellular mechanisms. The results are expected to be applicable to other disorders of muscles, joints and soft tissues. ? ? ?
The clinical standards for MRI studies of pathology in muscles and soft tissues are based on changes in T2 relaxation. These methods are useful because of their sensitivity to a wide range of mechanisms and good anatomical resolution, but this generality means they are unable to identify specific pathological processes in the affected areas. This project will systematically explore a broad range of MR imaging and spectroscopic methods to increase the specificity of a palette of MR methods by combining MR information and correlations with known perturbations in muscle. Models of dystrophic muscle will be used primarily and the potential benefits in this disease will be the first to be developed.
Showing the most recent 10 out of 61 publications
