Mitochondrial Genomes in Aging & Neurodegeneration

衰老中的线粒体基因组

• 批准号: 6741600
• 负责人: JAMES PEPPER BENNETT
• 金额: $ 26.71万
• 依托单位: GENCIA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6741600
• 关键词: RNA interference; aging; biotechnology; cell line; fibroblasts; gene therapy; mitochondrial DNA; mitochondrial disease /disorder; neural degeneration; neurons; oxidative stress; phenotype; technology /technique development; therapy design /development; transfection

DESCRIPTION (provided by applicant): Substantial evidence exists to support the hypothesis that oxidatively-damaged mitochondrial genomes contribute to the pathophysiology of aging and neurodegeneration. Damaged mitochondrial genes and mitochondrial oxidative stress contribute to or are primarily causal in bioenergetic failure of tissues, premature cell death of non-mitotic muscle cells and neurons and premature cell senescence through telomere dysfunction in dividing tissues. This STTR project further develops novel technologies of mitochondrial genome transfection ("mitofection") and mitochondrial genome removal ("mitoclean") towards commercialization. Three Aims will be addressed. In Aim 1 mitofection technology will be optimized with respect to transfection parameters. In Aim 2, the feasibility of combined RNAi-based gene silencing and mitofection to replace pathogenic mtDNA with wild-type mtDNA and correct abnormal metabolic phenotype will be demonstrated. In Aim 3, RNAi-based gene silencing will be used to produce mtDNA-free (rho0) lines of human primary neurons and fibroblasts that will serve as unique platforms for therapeutic development. This group has already demonstrated the feasibility of both major technologies. The outcome of this proposal will be a unique ability to manipulate the entire mitochondrial genome in mitochondria of cells. From this will develop methodologies for mitochondrial gene replacement therapies to reverse deleterious effects of aging and to prevent neurodegeneration. The results of this Phase I STTR will yield results that can readily be expanded into a Phase II proposal. Both "Mitofection" and "Mitoclean" are technologies that are scientifically compelling and applicable to multiple tissues, neural and non-neural. The interaction between Gencia and University of Virginia CSND is already well established and productive.

描述（由申请人提供）：存在大量证据支持以下假设：氧化损伤的线粒体基因组有助于衰老和神经变性的病理生理学。受损的线粒体基因和线粒体氧化应激导致或主要导致组织的生物能衰竭、非有丝分裂肌肉细胞和神经元的过早细胞死亡以及分裂组织中端粒功能障碍导致的细胞过早衰老。该 STTR 项目进一步开发了线粒体基因组转染（“mitofection”）和线粒体基因组去除（“mitoclean”）的新技术，以实现商业化。将解决三个目标。目标 1 将针对转染参数优化有丝转染技术。在目标 2 中，将证明结合基于 RNAi 的基因沉默和有丝转染以野生型 mtDNA 替换致病性 mtDNA 并纠正异常代谢表型的可行性。在目标 3 中，基于 RNAi 的基因沉默将用于产生人类原代神经元和成纤维细胞的无 mtDNA (rho0) 系，这些系将作为治疗开发的独特平台。该小组已经证明了这两项主要技术的可行性。该提案的结果将是操纵细胞线粒体中整个线粒体基因组的独特能力。由此将开发线粒体基因替代疗法的方法，以逆转衰老的有害影响并预防神经退行性变。第一阶段 STTR 的结果将产生可以轻松扩展到第二阶段提案的结果。 “Mitofection”和“Mitoclean”都是具有科学说服力的技术，适用于多种组织、神经和非神经组织。 Gencia 和弗吉尼亚大学 CSND 之间的互动已经建立并富有成效。