MINOCYCLINE IN 400 SUBJECTS WITH ALS

米诺环素治疗 400 名 ALS 患者

• 批准号: 7376455
• 负责人: Mark B. Bromberg
• 金额: $ 0.93万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7376455
• 关键词: antibacterial agents; death; enzymes; genes; genetically modified animals; human; laboratory mouse; model; tetracyclines

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Amyotrophic lateral sclerosis leads to degeneration of the voluntary motor system and death on average in 3 years. The course is progressive with a decline in function with time. There is no cure or known treatment that significantly improves function. The prevalence is 4-6 cases per 100,000 with an incidence of 0.4 to 1.8 per 100,000. The majority of ALS cases are sporadic. However, 10-15% are inherited as an autosomal dominant trait known as familial ALS (FALS). Of these, 25% are associated with a defect in the gene encoding the enzyme copper-zinc superoxide dismutase (SOD1). After discovery of mutant SOD1 in FALS, a transgenic mouse model was developed using the same gene. The SOD1 FALS rodent model has become an important method of pathological study and therapeutic drug screening in ALS. The sporadic and familial forms of human ALS are clinically and pathologically similar. Minocycline was selected for this study because its effects may inhibit motor nerve degeneration at several points. It likely inhibits cell death pathways by preventing both pro-apoptotic and pro-inflammatory enzyme activation. It inhibits release of mitochondrial cytochrome c and inhibits p38 mitogen activated protein (MAP) kinase, thus reducing cyclical activation and production of caspase enzymes, microglia, cytokines and oxidative species. It slows deterioration in several models of neurodegeneration, including ALS. It has neuroprotective benefit in experimental ischemia, and it has proven efficacy in human inflammatory arthritis, separate from its antibiotic properties. Hypothesis: Neuronal death in ALS may include apoptosis. Minocycline has shown anti-apoptotic effects and has slowed the rate of progression in a transgenic mouse model of ALS. Specific Aim 1: Minocycline will slow the rate of progression in ALS by 15%. Specific Aim 2: Minocycline will be tolerated at 200 mg/BID.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。肌萎缩性的侧索硬化症导致自愿运动系统的退化，并在3年​​内平均死亡。该课程是渐进的，随着时间的流逝，功能下降。没有明显改善功能的治疗或已知治疗方法。患病率为每100,000例4-6例，发病率为0.4至1.8，每100,000例。大多数ALS病例都是零星的。然而，10-15％的遗传为常染色体显性特征，称为家族性ALS（fals）。其中，有25％与编码铜锌超氧化物歧化酶（SOD1）的基因缺陷有关。在伪造中发现突变体SOD1后，使用相同基因开发了转基因小鼠模型。 SOD1虚拟啮齿动物模型已成为ALS中病理研究和治疗药物筛查的重要方法。人类ALS的零星和家族形式在临床和病理上是相似的。 选择米诺环素进行本研究，因为它的作用可能会在几个点抑制运动神经变性。它可能通过防止促凋亡和促炎酶激活来抑制细胞死亡途径。它抑制线粒体细胞色素C的释放，并抑制p38有丝分裂原活化蛋白（MAP）激酶，从而减少周期性激活和caspase酶的产生，小胶质细胞，细胞因子和氧化物种。它减慢了包括ALS在内的几种神经变性模型中的恶化。它在实验性缺血中具有神经保护作用，并且在人类炎症性关节炎中已证明有效性，与其抗生素特性分开。 假设：ALS中的神经元死亡可能包括凋亡。米诺环素显示出抗凋亡作用，并在ALS的转基因小鼠模型中降低了进展速率。具体目标1：米诺环素将使ALS的进展速度降低15％。具体目标2：米诺环素的耐受性为200 mg/bid。