Studies Of Hereditary Neurological Disease

神经遗传学分部的目的是调查遗传性神经疾病的原因，目的是为这些疾病开发有效的治疗方法。特别感兴趣的研究领域包括聚谷氨酰胺扩张性疾病(亨廷顿病、肯尼迪病和脊髓小脑性共济失调)、脊髓性肌萎缩症、夏科-玛丽-牙病、肌营养不良、遗传性运动神经元病和弗里德里希共济失调。在细胞培养和其他模型系统中对疾病机制进行了研究。一个相关的研究领域是雄激素对肌肉力量和运动神经元存活的影响机制。遗传外展计划旨在识别和描述患有遗传性神经疾病的患者和家庭的特征。庆大霉素治疗Duchenne肌营养不良症患者的试验已经完成，预计将进行进一步的治疗试验。过去一年的具体研究成果包括：(1)我们发现聚谷氨酰胺扩张性神经退行性疾病的发病机制涉及一个关键的核因子(CBP)和细胞过程(蛋白质乙酰化)，我们已经确定了减轻聚谷氨酰胺毒性的治疗方法(组蛋白脱乙酰酶抑制和RNA抑制)。(2)在聚谷氨酰胺病细胞培养模型中，我们进一步刻画了神经元死亡的途径。(3)我们在培养的神经细胞中发现了雄激素刺激的特定因子，它们是促进运动神经元存活的候选因子。(4)我们帮助缩小了分别定位于7号和9号染色体的常染色体显性遗传性轴索性神经病和运动神经元病的遗传缺陷的搜索范围，并收集了遗传性神经病和声带瘫痪(Charcot-Marie-Tooth病，2C型)的家系进行遗传连锁分析。 (5)我们开发了一项针对Friedreich‘s共济失调患者的抗氧化剂(艾地苯酮)治疗试验。(6)我们进行了庆大霉素治疗Duchenne肌营养不良症患者的试验，并在该疾病的小鼠模型MDX中表现出行为缺陷。(7)我们已经建立了脊髓和延髓肌萎缩(肯尼迪病)的小鼠模型。(8)我们已经克隆了一种维生素C转运蛋白的基因，它可能与神经退行性疾病有关。

The purpose of the Neurogenetics Branch is to investigate the causes of hereditary neurological diseases, with the goal of developing effective treatments for these disorders. Particular areas of research interest include the polyglutamine expansion diseases (Huntington's disease, Kennedy's disease, and spinocerebellar ataxia), spinal muscular atrophy, Charcot-Marie-Tooth disease, muscular dystrophy, hereditary motor neuron disease, and Friedreich's ataxia. The disease mechanisms are studied in cell culture and other model systems. A related area of investigation is the mechanism of androgen effects on muscle strength and motor neuron survival. A genetic outreach program is intended to identify and characterize patients and families with hereditary neurological diseases. A trial of gentamicin treatment in patients with Duchenne muscular dystrophy has been completed, and further therapeutic trials are anticipated. Specific research accomplishments in the past year include the following: (1) We have implicated a critical nuclear factor (CBP) and cellular process (protein acetylation) in the pathogenesis of polyglutamine expansion neurodegenerative disease, and we have identified treatments (histone deacetylase inhibition and RNA inhibition) that mitigate polyglutamine toxicity. (2) We have further characterized the pathway of neuronal death in a cell culture model of polyglutamine disease. (3) We have identified specific factors stimulated by androgens in cultured neuronal cells, which are candidates for promoting motor neuron survival. (4) We have helped to narrow the search for the genetic defects responsible for autosomal dominant forms of axonal neuropathy and motor neuronopathy that are mapped to chromosomes 7 and 9 respectively, and we have gathered families with hereditary neuropathy and vocal fold paralysis (Charcot-Marie-Tooth disease type 2C) for genetic linkage analysis. (5) We have developed a trial of anti-oxidant (idebenone) therapy for patients with Friedreich's ataxia. (6) We have carried out a trial of gentamicin treatment in patients with Duchenne muscular dystrophy, and characterized a behavioral deficit in mdx, a mouse model for this disease. (7) We have created a mouse model of spinal and bulbar muscular atrophy (Kennedy's disease). (8) We have cloned the gene for a vitamin C transporter, which may be involved in neurodegenerative disease.