Development of therapies to retard Parkinson's disease

开发延缓帕金森病的疗法

• 批准号: 7166047
• 负责人: TAKAO YAGI
• 金额: $ 28.81万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7166047
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animal Model; Applications Grants; Cells; Clinical; Complex; Condition; Cytochrome c Reductase; Disease; Dopaminergic Cell; Enzymes; Functional disorder; Genes; Goals; Grant; Link; Mammalian Cell; Mitochondria; Mus; Nerve; Oxidoreductase; Parkinson Disease; Primates; Procedures; Quinones; Rattus; Resistance; Respiratory Chain; Respiratory physiology; Rodent; Rodent Model; Rotenone; Saccharomyces cerevisiae; Symptoms; Therapeutic; benzoquinone; dopaminergic neuron; inhibitor/antagonist; motor disorder; novel; prevent; respiratory; therapy development; tool

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a late-onset, progressive motor disease marked by relatively selective nigrostrial dopaminergic degradation. Recent studies showed a link between PD and deficiency of the mitochondrial NADH dehydrogenase (complex I). It has been demonstrated that administration of agents that cause complex I inhibition (such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone) induces PD-like symptoms in primates or rodents. It is, therefore, anticipated that relieving dopaminergic cells of harmful effects caused by the dysfunction of complex I may provide a novel remedy for PD. Mitochondria of Baker's yeast, Saccharomyces cerevisiae, lack complex I but instead has the rotenone-insensitive NADH dehydrogenase (Ndi1). The applicants have shown that Ndi1 restores respiratory function to complex I-deficient mammalian cells and renders the respiratory chain resistant to complex I inhibitors. In addition, Ndi1 has been successfully introduced into dopaminergic nerve rat PC12 and mouse MN9D cells without impairing their capability of differentiation. In this proposal, the applicants will employ the Ndi1 enzyme as a therapeutic tool to retard PD and investigate its potential using animal models for PD. The studies during this grant term are as follows: (1) Refinement of the optimum conditions of the Ndi1 expression in nigral dopaminergic neurons of rodents. (2) Suppression of PD's disease like symptoms in rodent models by the Ndi1 expression.

描述（由申请人提供）：帕金森氏病（PD）是一种晚期发作的，进行性运动疾病，其标志性相对选择性染色性多巴胺能降解。最近的研究表明，PD与线粒体NADH脱氢酶缺乏之间的联系（复杂I）。已经证明，引起复杂I抑制剂的药物（例如1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）或Rotenone）会诱导灵长类动物或啮齿动物的PD样症状。因此，预计可以缓解由复合物功能障碍引起的有害作用的多巴胺能细胞可能为PD提供新颖的疗法。 贝克酵母的线粒体，酿酒酵母的糖疗法缺乏复杂的I，但具有不敏感的NADH脱氢酶（NDI1）。申请人表明，NDI1恢复了复杂的I缺陷型哺乳动物细胞的呼吸功能，并使对复合物I抑制剂具有抗性。此外，NDI1已成功地引入了多巴胺能神经大鼠PC12和小鼠MN9D细胞，而不会损害其分化能力。在此提案中，申请人将使用NDI1酶作为治疗工具来延迟PD并使用PD动物模型调查其潜力。 此授予期限的研究如下： （1）在啮齿动物的nigral多巴胺能神经元中NDI1表达的最佳条件的细化。 （2）通过NDI1表达抑制啮齿动物模型中PD疾病的症状。