Development of therapies to retard Parkinson's disease

开发延缓帕金森病的疗法

• 批准号: 7004553
• 负责人: TAKAO YAGI
• 金额: $ 29.67万
• 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/7004553
• 关键词: NAD(P)H dehydrogenase; Parkinson' s disease; adeno associated virus group; biotechnology; biotherapeutic agent; dopamine; enzyme induction /repression; fungal proteins; gene therapy; immune response; inflammation; laboratory mouse; laboratory rat; longitudinal animal study; methylphenyltetrahydropyridine; nervous system disorder therapy; neurons; neuroprotectants; neurotrophic factors; stereotaxic techniques; substantia nigra; therapy design /development; transfection /expression vector

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）：帕金森病（PD）是一种迟发性进行性运动疾病，其特征是相对选择性的黑质脑多巴胺能降解。最近的研究表明 PD 与线粒体 NADH 脱氢酶（复合物 I）缺乏之间存在联系。已经证明，施用引起复合物 I 抑制的药物（例如 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 或鱼藤酮）会在灵长类动物或啮齿类动物中诱导 PD 样症状。因此，预计减轻多巴胺能细胞由复合物 I 功能障碍引起的有害影响可能为 PD 提供新的治疗方法。 面包酵母（酿酒酵母）的线粒体缺乏复合物 I，但具有对鱼藤酮不敏感的 NADH 脱氢酶 (Ndi1)。申请人已经证明，Ndi1可以恢复复合物I缺陷的哺乳动物细胞的呼吸功能，并使呼吸链对复合物I抑制剂具有抗性。此外，Ndi1已成功导入多巴胺能神经大鼠PC12和小鼠MN9D细胞中，且不损害其分化能力。在该提案中，申请人将采用 Ndi1 酶作为延缓帕金森病的治疗工具，并利用帕金森病动物模型研究其潜力。 本资助期内的研究情况如下： (1)啮齿动物黑质多巴胺能神经元Ndi1表达最佳条件的细化。 (2)通过Ndi1表达抑制啮齿动物模型中的PD疾病样症状。