A whole body model of Pol III-related leukodystrophy

项目摘要 RNA聚合酶（Pol）III相关的脑白质营养不良是一种最近发现的常染色体隐性遗传病， 一种神经退行性疾病，其导致髓鞘形成不足，具有不同的疾病发作和严重程度。疾病 通常在儿童时期根据神经缺陷（包括发育迟缓、认知功能障碍） 退化，运动功能和智力残疾的逐步下降。其他临床特征 可能包括近视、牙齿发育不全和内分泌异常。对疾病机制的理解是 目前缺乏，进展受到缺乏动物模型的限制。最近的工作已经 产生了Pol III相关脑白质营养不良的谱系特异性基因敲入小鼠模型， 在患者中发现的疾病特征和相对轻微的病程。然而，这种模式缺乏毛电机 缺陷和小脑表型通常与更严重的疾病相关。Pol III相关 脑白质营养不良患者在所有体细胞中表达突变的Pol III亚基，但该疾病主要是 仅限于中枢神经系统。因此，为了更好地模拟人类疾病， 基因敲入小鼠。这种小鼠模型表现出严重的运动缺陷和更严重的疾病 当然了这项建议的目标是描述这些患者的行为和神经病理表型。 小鼠和分析Pol III在神经细胞群中的转录变化，以开发一种分子生物学方法。 了解疾病的发病机制。此外，我们还将测试一种基因策略， 转录和疾病表型。这些研究将大大提高对 Pol III相关脑白质营养不良的发病机制，并将提供用于测试的全身模型系统 针对疾病的治疗方法。

Project Summary RNA polymerase (Pol) III-related leukodystrophy is a recently identified autosomal recessive neurodegenerative disorder that causes hypomyelination with variable disease onset and severity. The disease is usually identified during childhood based on neurological deficits that include developmental delay, cognitive regression, a progressive decline in motor function and intellectual disability. Additional clinical characteristics can include myopia, hypodontia and endocrine abnormalities. An understanding of the disease mechanisms is currently lacking and progress has been limited by the absence of an animal model. Recent work has generated a lineage-specific knock-in mouse model of Pol III-related leukodystrophy that exhibits a subset of disease features found in patients and a relatively mild disease course. However, this model lacks gross motor defects and cerebellar phenotypes that are generally associated with more severe disease. Pol III-related leukodystrophy patients express mutant Pol III subunits in all somatic cells yet the disease is predominantly limited to the central nervous system. Thus, to better model the human disease, a conditional whole-body knock-in mouse was developed. This mouse model exhibits gross motor defects and a more severe disease course. The goals of this proposal are to characterize behavioral and neuropathological phenotypes of these mice and to profile Pol III transcriptional changes in neural cell populations to develop a molecular understanding of disease pathogenesis. In addition, we will test a genetic strategy for suppression of transcriptional and disease phenotypes. These studies will significantly enhance understanding of the pathogenesis of Pol III-related leukodystrophy and will provide a whole-body model system for testing therapeutic approaches targeting the disease.