RILUZOLE MOA: TARGETS FOR IMPROVED NEUROPROTECTIVE DRUGS

利鲁唑 MOA：改进神经保护药物的目标

• 批准号: 6882749
• 负责人: ANN E SLUDER
• 金额: $ 25.38万
• 依托单位: CAMBRIA BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6882749
• 关键词: Caenorhabditis elegans; alternatives to animals in research; amyotrophic lateral sclerosis; biological models; chemical structure function; drug adverse effect; drug resistance; drug screening /evaluation; genetic mapping; genetic polymorphism; helminth genetics; intermolecular interaction; neuroprotectants

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is an aggressive neurodegenerative disease of motor neurons that results in progressive muscle weakness, paralysis, and ultimately death, usually within five years of disease onset. Late stage ALS patients require extensive supportive care, placing immense emotional and economic burdens on patients and their families. Riluzole, the only drug currently approved for the treatment of ALS, provides only a modest extension of 2 to 3 months in life expectancy for ALS patients, and hepatotoxicity is a significant side effect limiting the drug's use. Biochemical and cellular studies have suggested a wide variety of potential targets for riluzole action, but the precise molecular mechanism of action (MO A) of this drug remains poorly defined. A more complete understanding of riluzole's molecular target(s) would be of great value in guiding the discovery of safer and more effective therapies for ALS. Genetic studies in the model nematode Caenorhabditis elegans have been successfully utilized to identify the targets and mechanistic pathways of a number of human Pharmaceuticals. Preliminary studies have demonstrated a significant effect of riluzole on C. elegans, and multiple independent genetic mutants resistant to the drug have been isolated. This Phase I SBIR project will complete the genetic analysis of these riluzole-resistance alleles in C. elegans, with the goal of characterizing riluzole's MOA and identifying riluzole targets that can be exploited for therapeutic discovery efforts. Two specific aims will be pursued: (1) Genetic mapping of the riluzole-resistance alleles will employ a combination of genetic recombination mapping and single-nucleotide polymorphism analysis. (2) Identification of the riluzole-resistance gene(s). Based on the genetic mapping results, a combination of candidate gene sequencing and, as needed, genetic transformation experiments will be used to identify the specific mutations conferring riluzole resistance. The molecular characterization of the riluzole-resistance gene(s) will identify one or more pathways for riluzole's action in a living model animal with a well-characterized nervous system. Subsequent Phase II efforts will (a) identify and evaluate the function of homologous mammalian genes, and (b) develop and implement new bioassays for the rational discovery of next-generation therapeutics for ALS and other neurodegenerative diseases.

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）是一种运动神经元的侵袭性神经退行性疾病，通常在发病5年内导致进行性肌肉无力、瘫痪并最终死亡。晚期ALS患者需要广泛的支持性护理，这给患者及其家人带来了巨大的情感和经济负担。利鲁唑是目前唯一被批准用于治疗ALS的药物，它只能适度延长ALS患者的预期寿命2 - 3个月，肝毒性是限制该药使用的一个显著副作用。生物化学和细胞研究已经提示利鲁唑作用的多种潜在靶点，但这种药物的精确分子作用机制（MO a）仍然不明确。更全面地了解利鲁唑的分子靶点将对指导发现更安全、更有效的ALS治疗方法具有重要价值。