Studies on Pol III-Associated Leukodystrophy

项目摘要 Pol III相关脑白质营养不良是一种与突变相关的常染色体隐性遗传神经退行性疾病 RNA聚合酶III（Pol III）的亚基。该疾病的临床和放射学谱仅 最近被定义。Pol III相关脑白质营养不良的特征是脑白色髓鞘形成不足， 这是一个严重的问题，并表现为运动功能的逐步下降，发育迟缓和智力残疾。 疾病发作通常发生在儿童时期，但诊断时的年龄范围很广，反映了变量 疾病的严重性和缓慢进展。其他临床特征包括近视、牙齿发育不全和 内分泌异常，但这些特征并不总是存在。发病机制是 未知且无可用的治疗选择。进一步了解这种疾病的进展受到限制， 缺乏模型系统。因此，本研究的目标是开发一种与Pol III相关的小鼠模型。 脑白质营养不良我们已经建立了一个基因敲入小鼠表达临床定义的Pol III相关基因。 脑白质营养不良突变我们将描述的行为，放射学和神经病理表型， 这些老鼠。表型变化将与突变对Pol III转录、tRNA和蛋白质的影响相关。 生物发生和蛋白质合成。此外，我们将测试一个模型，用于对Pol III相关的基因抑制。 脑白质营养不良表型这些研究将大大提高对Pol发病机制的认识， III型相关脑白质营养不良，并将提供一个模型系统，用于测试治疗方法的目标是 疾病

Project Summary Pol III-associated leukodystrophy is an autosomal recessive neurodegenerative disease linked to mutations in subunits of RNA polymerase III (Pol III). The clinical and radiologic spectrum of the disorder has only recently been defined. Pol III-associated leukodystrophy is characterized by hypomyelination of cerebral white matter and presents as a progressive decline in motor function, developmental delay and intellectual disability. Disease onset typically occurs during childhood but the age range at diagnosis is broad, reflecting the variable severity and slow progression of the disease. Other clinical characteristics include myopia, hypodontia and endocrine abnormalities but these features are not always present. The mechanism of pathogenesis is unknown and no therapeutic options are available. Further progress in understanding this disease is limited by the lack of model systems. Thus, the goal of this research is to develop a mouse model of Pol III-associated leukodystrophy. We have created a knock-in mouse expressing clinically-defined Pol III-associated leukodystrophy mutations. We will characterize the behavioral, radiologic and neuropathologic phenotypes of these mice. Phenotypic changes will be correlated with the impact of the mutation on Pol III transcription, tRNA biogenesis and protein synthesis. In addition, we will test a model for genetic suppression of Pol III-associated leukodystrophy phenotypes. These studies will significantly enhance understanding of the pathogenesis of Pol III-associated leukodystrophy and will provide a model system for testing therapeutic approaches targeting the disease.