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Development of low-molecular-weight compound therapy for polyglutamine diseases

多聚谷氨酰胺疾病低分子复合疗法的开发

基本信息

批准号：
16390250
负责人：
DOYU Manabu
金额：
$ 9.34万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390250/
关键词：
motor neuron spinal and bulbar muscular atrophy amyotrophic lateral sclerosis polyglutamine LHRH analog Dorfin VCP p97 gene expression profiles 臨床試験アンドロゲン受容体バイオマーカー CAGリピートトランスジェニックマウス分子シャペロンヒストン脱アセチル化ユビキチンリガーゼ

项目摘要

In this study, we elucidated the pathophysiology of adult-onset motor neuron diseases, and developed pathogenesis-based therapy for them. Immunohistochemically using 1C2, an anti-polyglutamine antibody, demonstrated that diffuse nuclear accumulation of mutant AR was far more frequent and extensive than NIs being distributed in a wide array of CNS nuclei, and in more visceral organs than thus far believed. Furthermore, the extent of diffuse nuclear accumulation of mutant AR in spinal motor neurons was closely related to CAG repeat length. Thus, diffuse nuclear accumulation of mutant AR apparently is a cardinal pathogenesis underlying neurodegeneration in SBMA. The degree of mutant AR accumulation in scrotal skin epithelial cells tended to be correlated with that in the spinal motor neurons in autopsy specimens, and it was well correlated with CAG repeat length and inversely correlated with the motor functional scale. In a randomized double-blind trial, LHRH analog treatment inhibited mutant AR protein accumulation in the scrotal skin, reduced serum level of creatine kinase, and improved the swallowing function of SBMA patients.As for amyotrophic lateral sclerosis (ALS), we calrified that valosin-containing protein (VCP) directly binds to Dorfin, a protein modifying ALS pathogenesis, and that VCP ATPase activity profoundly contributes to the E3 activity of Dorfin. Using microarray technology combined with laser-captured microdissection, gene expression profiles of degenerating spinal motor neurons isolated from autopsied patients with sporadic ALS were examined. Downregulated genes included those associated with cytoskeleton/axonal transport, transcription, and cell surface antigens/receptors. In contrast, cell death-associated genes were mostly upregulated.

在这项研究中，我们阐明了成人发病的运动神经元疾病的病理生理学，并开发了基于发病机制的治疗方法。使用抗多聚谷氨酰胺抗体1C 2的免疫组化表明，突变AR的弥漫性核积聚比分布在广泛的中枢神经系统核中的NI更频繁和广泛，并且在更多的内脏器官中的分布比迄今为止认为的要多。此外，突变型AR在脊髓运动神经元中的弥漫性核积聚程度与CAG重复序列长度密切相关。因此，突变型AR的弥散性核积聚显然是SBMA神经变性的主要发病机制。阴囊皮肤上皮细胞中突变型AR的蓄积程度与尸检标本中脊髓运动神经元中的蓄积程度有相关性，且与CAG重复序列长度呈正相关，与运动功能评分呈负相关。在一项随机双盲试验中，LHRH类似物治疗可抑制突变型AR蛋白在阴囊皮肤中的积聚，降低血清肌酸激酶水平，并改善SBMA患者的吞咽功能。至于肌萎缩侧索硬化症（ALS），我们证实，含缬沙汀蛋白（VCP）直接与Dorfin结合，Dorfin是一种调节ALS发病机制的蛋白质，VCP ATP酶活性对Dorfin的E3活性有重要的影响。使用微阵列技术结合激光捕获显微切割，从散发性ALS尸检患者中分离的退化脊髓运动神经元的基因表达谱进行了研究。下调的基因包括与细胞骨架/轴突运输、转录和细胞表面抗原/受体相关的基因。相反，细胞死亡相关基因大多上调。