Molecular Basis of Mitochondrial Myopathy and Animal Models Related to the Energy Abnormality

线粒体肌病的分子基础和能量异常相关的动物模型

基本信息

批准号：
13670853
负责人：
KOGA Yasutoshi
金额：
$ 2.3万
依托单位：
KURUME UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670853/
关键词：
Mitochondrial stroke endothelial dyfunction Nitric oxide Mitochondrial disease mitochondrial tRNA mutation L-arginine RNA19 Klotho Knockout mouse

项目摘要

Mitochondrial myopathy is a mutisystem disorders characterized by dysfunctions of mitochondrial energy metabolism. To investigate and clarify the molecular basis of mitochondrial myopathy, the creation of animal models is essential. In 1997, Klotho gene knockout mice have been developed as a model of human aging. However, there are no reports to investigate the molecular mechanism of abnormality in the mitochondrial energy metabolism in Klotho gene knockout mice. In this project, we planned to investigate the mitochondrial energy metabolism in Klotho gene knockout mice including mitochondrial respiratory chain enzyme, cytochrome contents, oxograph, uptake of neurotransmitters in synaptosome, muscle histochemistry and mitochondrial DNA abnormalities to evaluate the relationship between aging and mitochondrial energy metabolism.MELAS, is a maternally-inherited mitochondrial multisystem disorder, characterized early onset stroke before age 20. Mitochondrial angiopathy demonstrating degene … More rative change with increased abnormal mitochondria in the endothelial cells of intramuscular small arteries and arterioles has been reported in many MELAS patients. However, the primary cause for stroke-like episodes in young MELAS patients - whether mitochondrial cytopathy, angiopathy, or both - remains controversial. Based on a hypothesis that stroke-like episodes in MELAS are caused by segmental impairment of vasodilation in intracerebral arteries, we administered L-arginine to MELAS in the acute phase of stroke. We reported that L-arginine therapy quickly improved the symptoms of stroke in MELAS, improved the microcirculation, and also reduced tissue injury from ischemia. We demonstrated the pharmacological effects of L-arginine on the acute phase of stroke-like episodes to determine whether the plasma concentrations of biological parameters including L-arginine, NOx, or ADMA, the important regulatory factors to the endothelial functions, are changed in patients with MELAS compared with normal subjects. L-arginine therapy improved the microcirculation to reduce tissue injury from ischemia, and therefore constitutes a new potential therapy for use in the acute phase of strokelike episodes in MELAS. Less

线粒体肌病是一种由线粒体能量代谢功能障碍为特征的犬种疾病。为了调查和阐明线粒体肌病的分子基础，动物模型的创建至关重要。 1997年，Klotho Gene基因敲除小鼠被开发为人类衰老的模型。但是，尚无报道研究克洛托基因基因敲除小鼠线粒体能量代谢中绝对性的分子机制。我们计划研究Klotho基因敲除小鼠中的线粒体能量代谢，包括线粒体呼吸链酶，细胞色素含量，氧化片，神经递质在突触体中的摄取，肌肉组织化学和线粒体dNA ersornorm intermant and contrial dna fressort and contrial dna fressord rom andir nim dna fernast ro.代谢。梅拉斯是一种主要具有的线粒体多系统疾病，表征了20岁以前的早期发作中风。线粒体血管病表现出degene的更为危险的变化，随着许多梅拉斯病人的内皮细胞中异常细胞的异常线粒体的增加，已有许多梅拉斯病人在许多梅拉斯患者中。但是，在年轻的Melas患者中引起中风样发作的主要原因 - 无论是线粒体细胞病，血管病还是两者 - 仍然存在争议。基于一个假设，即MELAS中的中风样发作是由脑动脉中血管舒张的分段损害引起的，我们在中风的急性期将L-精氨酸施用到Melas。我们报告说，L-精氨酸疗法迅速改善了Melas中风的症状，改善了微循环，还减少了缺血性的组织损伤。我们证明了L-精氨酸对中风样发作的急性期的药物作用，以确定包括L-精氨酸，NOX或ADMA在内的生物学参数的等离子体浓度，与正常受试者相比，MELAS患者的内皮功能的重要调节因素是否会改变。 L-精氨酸治疗改善了微循环，以减少缺血的组织损伤，因此构成了一种在Melas中strokelike发作的急性期使用的新潜在疗法。较少的