时  间：   2018年4月19日, 14:00-15:30

地  点：   清华大学生物新馆143

讲座嘉宾：Dr. Robert W. Burgess, Professor, The Jackson Laboratory, Bar Harbor, ME

主持人：贾怡昌，清华-IDG/麦戈文脑科学研究院研究员

题目：Mechanisms of axon degeneration and preclinical studies in mouse models of inherited peripheral neuropathy

摘要：Precision genetic models made in mice can help define the mechanisms of human diseases and can be used in preclinical studies to test treatment options. We have made mouse models of the inherited peripheral neuropathy, Charcot-Marie-Tooth disease type 2D (CMT2D) for these purposes. ?The disease is caused by dominant mutations in the ubiquitous housekeeping gene glycyl tRNA synthetase, (GARS), which charges glycine onto its cognate tRNAs for translation. Our genetic characterization of these mice indicates that the mutation creates a pathogenic gain-of-function mutation. Therefore, increasing the normal function of GARS does not affect the phenotype. ?Instead, successful therapies need to selectively target the mutant form. ?We have developed an allele-specific knockdown approach, using RNAi delivered by the viral vector AAV9 to accomplish this. ?Treatment of mice before the onset of disease can almost completely prevent the neuropathy, and treatment after the onset of disease still has benefit, increasing the function of the remaining axons. This approach is potentially translational, and also addresses the underlying mechanisms of the disease, such as the developmental timing and cell autonomy of the neurodegeneration.