First generation mouse models of mtDNA disease: Testing genotype/phenotype predictions

线粒体疾病包括影响婴儿、儿童和成人的各种遗传性疾病。这些疾病是由线粒体产生的能量缺陷造成的，线粒体是所有细胞中具有自己独特DNA的微小结构。这种线粒体DNA只从我们的母亲那里遗传。为了为细胞正常运作提供能量，线粒体和核基因会在线粒体中产生特殊的酶。在最严重的情况下，线粒体疾病会导致婴儿出现多系统衰竭。成人形式没有那么严重，症状包括癫痫、心肌病、迟发性失明或耳聋，通常还有糖尿病。我们不明白为什么不同的线粒体突变会导致如此不同的症状，而且没有一种治疗方法总是成功的。线粒体DNA的不同寻常的特征意味着它仍然超出了现在通常用于培育基因改变的小鼠的技术的范围。这些所谓的“老鼠模型”是更好地了解人类疾病的强大工具，更重要的是，它使实验疗法得以测试和改进。这项资助提出了一种制造这种小鼠模型的新方法，首次允许制造出具有不同程度线粒体功能缺陷的小鼠来模拟人类疾病。在这项拟议的工作中，来自不同小鼠物种的线粒体将被引入实验室小鼠。这种不同寻常的方法是基于研究人员之前的工作，他们已经证明这会在培养的小鼠细胞中产生有缺陷的线粒体。这些小鼠将被允许衰老，随着动物年龄的增长，不同器官的线粒体功能将得到测试。其次，将在培养细胞和突变体中产生一系列线粒体DNA突变，以使其他小鼠能够准确地模拟各种人类疾病。

Mitochondrial diseases comprise a diverse group of inherited diseases affecting infants, children and adults. These disorders result from defective energy production by the mitochondria, tiny structures in all cells which have their own unique DNA. This mitochondrial DNA is inherited only from our mothers. To make energy for cells to function normally, special enzymes are produced in the mitochondria from mitochondrial and nuclear genes. In their most severe form mitochondrial disease results in infants with muti-system failure. Adult forms are less severe, with symptoms including epilepsy, cardiomyopathy, late-onset blindness or deafness, and commonly diabetes. We do not understand why different mitochondrial mutations result in such diverse symptoms, and no therapies have been consistently successful. Unusual features of mitochondrial DNA has meant that it has remained beyond the reach of techniques which are commonly used now to produce mice with altered genes. These so-called 'mouse models' are powerful tools to better understand human diseases and importantly, to enable experimental therapies to be tested and improved. This grant proposes a novel method of producing such mouse models, for the first time allowing mice with different levels of defective mitochondrial function to be produced to model the human diseases. In the proposed work, mitochondria from different mouse species will be introduced into laboratory mice. This unusual approach is based on previous work by the investigators who have shown that this produces defective mitochondria in cultured mouse cells. These mice will be allowed to age and the function of mitochondria from different organs tested as the animals age. Secondly, a range of mitochondrial DNA mutations will be produced in cultured cells and mutants selected to make other mice which should accurately model the diverse human diseases.