Studies Of Hereditary Neurological Disease

遗传性神经系统疾病的研究

• 批准号: 7143886
• 负责人: Kenneth H Fischbeck
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7143886
• 关键词: Drosophilidae; Friedreich' s ataxia; Huntington' s disease; cerebellar ataxia /dyskinesia; clinical trial phase I; congenital neuromuscular disorder; drug screening /evaluation; gene mutation; genetic disorder; genetic mapping; genetic screening; hereditary motor and sensory neuropathy; homopeptide; human subject; human therapy evaluation; laboratory mouse; medical outreach /case finding; molecular pathology; muscular dystrophy; nervous system disorder chemotherapy; neurogenetics; nucleic acid repetitive sequence; patient oriented research; quinones; tissue /cell culture; transport proteins

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 genetic outreach program allows the identification and characterization of patients and families with hereditary neurological diseases. A trial of idebenone treatment in Friedreich's ataxia is in progress. Further therapeutic trials are anticipated. Specific research accomplishments in the past year include the following: (1) We further characterized the mechanism of neuronal death in cell culture and Drosophila models of polyglutamine disease and investigated the role of profilin in this mechanism. (2) We characterized the biochemical effects and clinical and pathological manifestations of a mutation in the transport protein dynactin in an autosomal dominant form of motor neuron disease. (3) We further characterized the clinical manifestations of motor neuronopathy due to mutations in glycyl-tRNA synthetase. (4) We further characterized the effects of protein kinase C mutations in patients with spinocerebellar ataxia. (5) We completed studies of X-linked Charcot-Marie-Tooth disease in transgenic mice and described a patient with unusually severe manifestations of this disease. (6) We further characterized the effects of histone acetylation and histone deacetylase inhibitors on the expression of SMN, the gene that is mutated in spinal muscular atrophy. (7) We completed a phase 1b chronic high dose tolerability study of idebenone therapy in patients with Friedreich's ataxia and developed a phase 2 protocol comparing high dose, low dose, and placebo treatment. (8) We helped in the development of an ataxia scale for measuring the response to treatment of patients with Friedreich's ataxia and related diseases.

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。遗传外展计划允许识别和描述患有遗传性神经疾病的患者和家庭的特征。艾地苯酮治疗Friedreich共济失调的试验正在进行中。预计还会有更多的治疗试验。过去一年的具体研究成果包括：(1)我们进一步研究了细胞培养中神经元死亡的机制和果蝇聚谷氨酰胺病模型，并研究了profilin在这一机制中的作用。(2)我们研究了一种常染色体显性遗传性运动神经元病中转运蛋白dynactin突变的生化效应、临床和病理表现。(3)进一步描述了甘氨酰-tRNA合成酶突变所致运动神经元病的临床表现。(4)我们进一步研究了蛋白激酶C突变在脊髓小脑性共济失调患者中的作用。(5)我们在转基因小鼠中完成了X连锁Charcot-Marie-Tooth病的研究，并描述了一例异常严重的该病患者。(6)进一步研究了组蛋白乙酰化和组蛋白脱乙酰酶抑制剂对脊髓性肌萎缩症突变基因SMN表达的影响。(7)我们完成了艾地苯酮治疗Friedreich‘s共济失调患者的1b期慢性高剂量耐受性研究，并制定了比较高剂量、低剂量和安慰剂治疗的第二阶段方案。(8)我们帮助开发了共济失调量表，用于衡量Friedreich‘s共济失调及相关疾病患者的治疗反应。