关键词：临床医学;医疗服务;症状和体征
摘 要：The goal of this work is to increase the availability of critical mouse models of human muscular dystrophy (MD) for both hypothesis testing and preclinical therapy development. Our multi-disciplinary team from The Jackson Laboratory (JAX) and the Children s National Medical Center (CNMC) has expertise in MD, repository management, mouse models, and preclinical testing. At JAX, Drs. Lutz and Cox have established the MD Repository (Aim1) to leverage JAX s considerable expertise and infrastructure to maintain and distribute MD mouse and information resources to the scientific community. In Aim 2 we are developing novel DMD transgenic mice, which model patients receiving successful exon-skipping therapies. We propose to address the fundamental, but often overlooked question related to the functionality of resulting Dystrophin molecules containing in-frame deletions that are expected to arise by successful treatment of patient mutations. Our transgenic experiments will model the best-case-scenario outcome for AO-mediated therapy in which one assumes that a particular compound is capable of 100effective exon-skipping to restore the reading frame. In Aim 3, we are generating congenic mdx mice to better model the symptoms of the human disease and to identify genetic modifiers that can alter disease onset and severity. In Aim 4, Dr. Nagaraju at CNMC is carrying out preclinical studies with three promising therapeutic compounds (GW501516, AICAR and Dantrolene) using key models developed at JAX. Overall, this program will greatly expand the accessibility and availability of mouse model resources for MD translational research and therapeutic development.