Disease Mechanisms of Pontocerebellar Hypoplasia Type 10

项目摘要/摘要 大脑或脊髓神经元的退化与许多无法治疗的神经疾病有关 并导致认知和运动功能逐渐下降，最终死亡。而在老年人中更常见 就个人而言，神经退行性疾病的发病情况多种多样，可以从儿童时期开始。没有有效的方法 对大多数患者的治疗，可能是由于我们对疾病病因学的有限理解。继承 神经退行性疾病通常由调节神经退行性疾病的rna结合蛋白的基因突变引起。 RNA生物发生。为了开发这类疾病的治疗方法，关键是要了解 RNA结合蛋白在正常和疾病状态下起作用，以及分子变化是否服从于 更正。 我们的初步数据表明，在遗传性疾病的情况下，mRNA的处理可能会受到显著影响 儿童期运动神经元变性。来验证我们的假设，即信使核糖核酸加工缺陷会导致儿科 运动神经元疾病，我们已经创建了基于人类干细胞和动物的模型来关联分子 随着疾病病理的变化。我们将应用高通量测序、电生理学、组织学和 用行为学方法建立我们的新疾病模型，以确定致病转录的mRNA亚型 作为RNA结合蛋白突变的结果表达，以及测试候选靶向基因- 以治疗为基础。

PROJECT SUMMARY/ABSTRACT Degeneration of brain or spinal cord neurons is associated with many untreatable neurological disorders and leads to a gradual decline in cognitive and motor function, and eventual death. While more prevalent in aged individuals, neurodegenerative disease onset is variable and can begin in childhood. There are no effective therapies for the majority of patients, likely due to our limited understanding of disease etiology. Inherited neurodegenerative disorders are commonly caused by genetic mutations in RNA binding proteins that regulate RNA biogenesis. In order to develop therapeutics for this class of disorders, it will be critical to understand how RNA binding proteins function in normal and diseased states, and whether molecular changes are amenable to correction. Our preliminary data suggests mRNA processing may be significantly affected in cases of inherited childhood motor neuron degeneration. To test our hypothesis that mRNA processing defects cause pediatric motor neuron disease, we have created human stem cell- and animal-based models to correlate molecular changes with disease pathology. We will apply high-throughput sequencing, electrophysiology, histology and behavioral approaches to our novel disease models to pinpoint pathogenic transcriptional mRNA isoforms expressed as a consequence of the RNA binding protein mutation as well as test a candidate targeted gene- based therapy.