Molecular Remedy of Mitochondrial Defects

线粒体缺陷的分子疗法

• 批准号: 8792528
• 负责人: TAKAO YAGI
• 金额: $ 46.15万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792528
• 关键词: Affect; Animal Model; Animals; Area; Axon; Biochemical; Blindness; Brain; Cessation of life; Complex; Cytochrome c Reductase; DNA Sequence Alteration; Data; Defect; Demyelinations; Disease; Disease Progression; Enzymes; Exhibits; Female; Flavin Mononucleotide; Functional disorder; Ganglion Cell Layer; Gene Expression; Genes; Goals; Grant; Health; Human; Human body; Infusion procedures; Investigation; Iron; Knowledge; Leber' s Hereditary Optic Neuropathy; Mitochondria; Mitochondrial Diseases; Modeling; Modification; Molecular; Mouse Strains; Multienzyme Complexes; Mus; Mutate; Mutation; NADH oxidase; Oxidative Phosphorylation; Penetrance; Phase; Prevention; Ranvier' s Nodes; Rattus; Recovery; Reporting; Research; Research Project Grants; Retina; Retinal Ganglion Cells; Rotenone; Staging; Structure; Sulfur; Symptoms; System; Techniques; Testing; Time; Tissues; Transgenic Mice; Vision; Visual impairment; Yeasts; base; cofactor; human disease; male; mitochondrial DNA mutation; oxidative damage; remyelination; repaired; research study; restoration; superior colliculus Corpora quadrigemina; therapy development

DESCRIPTION (provided by applicant): The overall goal of this grant is to seek molecular therapies for diseases resulting from defects of the mitochondrial oxidative phosphorylation system. Complex I is the first of five enzyme complexes that comprise the oxidative phosphorylation system. It has the most intricate structure with 45 different subunits (of these, 7 subunits are mitochondrially encoded (designated ND1-6 and 4L)), one FMN and eight iron- sulfur clusters as cofactors. Complex I defects are involved in many human mitochondrial diseases. Leber's hereditary optic neuropathy (LHON) is recognized as the frequently occurring complex I disease. A new animal model has been developed that involves infusion of rotenone-biobeads into the superior colliculus of the rat brain. Symptoms typical of LHON were observed in the animals, most notably, severely impaired vision. At the same time, there was clearly disorganization of the node of Ranvier as well as demyelination of the RGC axons. However, loss of vision was not accompanied by the hallmarks of LHON such as thinner retinal ganglion cell (RGC) layer and death of RGC which only occurred at a later stage. Furthermore, delivery of the yeast alternative NADH dehydrogenase gene (NDI1) into the rat brain restored the vision to normal level with concomitant reorganization of the node of Ranvier and remyelination of the RGC axons. These findings form the basis of this research project. During this grant term, focus will be made on LHON research with the following specific aims. (i) To investigate mechanism of LHON by using the rat models by administration of mutated human or rat ND4 gene to the retina or rotenone biobeads infusion in the superior colliculus. (ii) To clarify whether the NDI1 gene expression can repair vision loss of the two LHON models and to determine repair window. (iii) To construct transgenic mouse strains carrying the mutated human or mouse ND4 gene for further investigation of LHON such as triggering factors.

描述（由申请人提供）：该资助的总体目标是寻求针对线粒体氧化磷酸化系统缺陷引起的疾病的分子疗法。复合物 I 是构成氧化磷酸化系统的五种酶复合物中的第一个。它具有最复杂的结构，有 45 个不同的亚基（其中 7 个亚基由线粒体编码（称为 ND1-6 和 4L））、1 个 FMN 和 8 个作为辅助因子的铁硫簇。复合体 I 缺陷与许多人类线粒体疾病有关。莱伯氏遗传性视神经病变（LHON）被认为是常见的复杂 I 性疾病。一种新的动物模型已经开发出来，该模型涉及将鱼藤酮生物珠注入大鼠大脑的上丘。在动物中观察到 LHON 的典型症状，最明显的是视力严重受损。同时，Ranvier结明显紊乱，RGC轴突脱髓鞘。然而，视力丧失并不伴随LHON的特征，例如视网膜神经节细胞（RGC）层变薄和RGC死亡，这些特征仅发生在后期。此外，将酵母替代性 NADH 脱氢酶基因 (NDI1) 输送到大鼠大脑中，可将视力恢复到正常水平，同时朗飞结重组和 RGC 轴突髓鞘再生。这些发现构成了该研究项目的基础。在此资助期内，重点将放在 LHON 研究上，其具体目标如下。 (i) 通过使用大鼠模型来研究 LHON 的机制，通过将突变的人或大鼠 ND4 基因施用到上丘的视网膜或鱼藤酮生物珠输注中。 (ii)阐明NDI1基因表达是否可以修复两种LHON模型的视力丧失并确定修复窗口。 (iii)构建携带突变的人或小鼠ND4基因的转基因小鼠品系，以进一步研究LHON，例如触发因素。

项目成果

Long-term evaluation of Leber's hereditary optic neuropathy-like symptoms in rotenone administered rats.

鱼藤酮给药大鼠莱伯遗传性视神经病样症状的长期评估。

• DOI: 10.1016/j.neulet.2014.12.004
• 发表时间: 2015
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Zhang,Li;Liu,Laura;Philip,AnnL;Martinez,JuanC;Guttierez,JuanC;Marella,Mathieu;Patki,Gaurav;Matsuno-Yagi,Akemi;Yagi,Takao;Thomas,BijuB
• 通讯作者: Thomas,BijuB