Studies on Pol III-Associated Leukodystrophy

项目摘要 Pol III相关性脑白质营养不良是一种与突变相关的常染色体隐性遗传性神经退行性疾病 在RNA聚合酶III(Pol III)的亚基中。这种疾病的临床和放射学谱系只有 最近才被定义。Pol III相关性脑白质营养不良的特征是脑白质髓鞘减少 表现为运动功能进行性下降、发育迟缓和智力残疾。 疾病通常发生在儿童时期，但确诊时的年龄范围很广，反映了变量 疾病的严重程度和缓慢发展。其他临床特征包括近视、牙量减少和 内分泌异常，但这些特征并不总是存在。其发病机制是 未知的，也没有治疗方案可用。对这种疾病的进一步了解受到以下因素的限制 缺乏模型系统。因此，本研究的目标是建立一种Pol III相关的小鼠模型。 脑白质营养不良。我们已经创造了一种敲入小鼠，表达临床定义的Pol III相关基因 脑白质营养不良突变。我们将描述其行为、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的影响相关 生物发生和蛋白质合成。此外，我们还将测试Pol III相关基因抑制的模型 脑白质营养不良表型。这些研究将大大加强对POL发病机制的了解 III相关性脑白质营养不良，并将提供一个模型系统，用于测试针对 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.