TRANSMITOCHONDRIAL MOUSE MODELS OF HUMAN DISEASE

人类疾病的传播线粒体小鼠模型

• 批准号: 6364630
• 负责人: Carl A. Pinkert
• 金额: $ 15.95万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6364630
• 关键词: confocal scanning microscopy; disease /disorder model; electroporation; gene deletion mutation; genome; histopathology; in situ hybridization; laboratory mouse; method development; microinjections; mitochondrial DNA; mitochondrial disease /disorder; model design /development; mutant; polymerase chain reaction; tissue /cell culture; transfection

DESCRIPTION (Provided by applicant): This project is designed to develop a novel mouse model of human mitochondrial disease. Genetic engineering and molecular biological techniques will be utilized to create heteroplasmic "transmitochondrial" mice harboring a mutant mitochondrial genome. This model and the procedures for mitochondrial transfer will be of considerable importance toward our understanding of a specific mitochondrial mutation, as well as leading to the development of novel strategies and therapies for human metabolic diseases influenced by aberrations in mitochondrial function or mutation. In pilot experiments, the ability to create transmitochondrial mouse models that transmit the heteroplasmic state to offspring in maternal lineages was identified. With the advent of gene transfer technologies and PCR-based procedures, this project will target the development of technology to establish a mouse model harboring a directed mitochondria DNA (mtDNA) deletion. Specific Aims include: (1) development and optimization of mitochondria transfection procedures, (2) transfer of transfected mitochondria (or cells) into mouse ova to produce heteroplasmic transmitochondrial mice that will recapitulate a deletion associated with human mtDNA-based disease - for which no animal model exists for study, and (3) characterization of transmitochondrial mouse lineages created over the course of this project. Production of heteroplasmic transmitochondrial deletion mutants will be a critical first step, facilitating the study of mitochondrial function and disease progression. Initially, this model will serve to explore disease pathogenesis and mitochondrial dynamics in an in vivo system. Ultimately, transmitochondrial mouse models will be used to explore the role of the mitochondrial genome in human metabolic disease processes and in the development of novel human gene therapies.

描述（由申请人提供）：该项目旨在开发 人类线粒体疾病的新型小鼠模型。 基因工程和 分子生物学技术将用于创建异质 带有突变线粒体基因组的“蒙木膜软骨”小鼠。 这个模型 线粒体转移的程序将是相当大的 对我们对特定线粒体突变的理解的重要性， 并导致人类的新型策略和疗法的发展 由线粒体功能的畸变影响的代谢疾病或 突变。 在试验实验中，创建丝木骨软骨的能力 将异质状态传播到母体后代的小鼠模型 鉴定了谱系。 随着基因转移技术的出现和 基于PCR的程序，该项目将针对技术的发展 建立带有定向线粒体DNA（mtDNA）的小鼠模型 删除。 具体目的包括：（1）开发和优化 线粒体转染程序，（2）转染的线粒体转移 （或细胞）进入小鼠OVA以产生异质性跨膜膜片状小鼠 这将概括与基于人类mtDNA的疾病相关的缺失 - 为此，没有动物模型进行研究，（3）表征 在该项目的整个过程中创建的多膜软骨小鼠谱系。 产生异质的多蒙蒙软骨缺失突变体将是一个 关键的第一步，促进线粒体功能的研究和 疾病进展。 最初，该模型将有助于探索疾病 体内系统中的发病机理和线粒体动力学。 最终， 蒙木膜软骨小鼠模型将用于探索 人类代谢疾病过程中的线粒体基因组和 新型人类基因疗法的发展。