Molecular Remedy of Mitochondrial Defects

线粒体缺陷的分子疗法

基本信息

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
项目类别：
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&apos 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&apos 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

项目摘要

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）：该赠款的总体目标是寻求因线粒体氧化磷酸化系统缺陷而导致的疾病的分子疗法。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45个不同亚基的最复杂的结构（其中7个亚基是用线粒体编码（指定的ND1-6和4L），一个FMN和8个铁硫簇作为辅因子。复杂的I缺陷涉及许多人类线粒体疾病。 Leber的遗传性视神经病变（LHON）被认为是经常发生的复合物I疾病。已经开发了一种新的动物模型，该模型涉及将烤面包酮 - 双子片输注到大鼠脑的上丘中。在动物中观察到了lhon的典型症状，最值得注意的是，视力严重受损。同时，Ranvier的节点以及RGC轴突的脱髓鞘显然存在混乱。然而，视力丧失并不伴随着Lhon的标志，例如较薄的视网膜神经节细胞（RGC）层和RGC死亡，而RGC的死亡仅发生在后期。此外，将酵母替代NADH脱氢酶基因（NDI1）递送到大鼠大脑中，将视力恢复到正常水平，并随着RANVIER节点的同时重组和RGC轴突的再髓增生。这些发现构成了该研究项目的基础。在此授予期限期间，将重点放在LHON研究上，并具有以下特定目标。（i）通过使用大鼠模型来研究LHON的机理，该模型通过将突变的人或大鼠ND4基因施用到视网膜或紫红酮的上丘中输注。（ii）澄清NDI1基因表达是否可以修复两个LHON模型的视力丧失并确定修复窗口。（iii）构建带有突变的人或小鼠ND4基因的转基因小鼠菌株，以进一步研究LHON，例如触发因素。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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