Manipulating the mitochondrial genome to investigate the impact of mtDNA mutations in cancer

操纵线粒体基因组以研究 mtDNA 突变对癌症的影响

• 批准号: EP/X035581/1
• 负责人: Payam Gammage
• 金额: $ 213.27万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX035581%2F1
• 关键词: Manipulating; mitochondrial; genome; investigate; impact

Mutations of mtDNA are present in ~60% of all tumours and have long been overlooked in cancer biology. Recent groundbreaking work from my lab has identified mtDNA mutations as a major phenotype-modifier across all cancers, and mtDNA mutations in colorectal cancer were linked to major extensions in lifespan, the first robust evidence for the clinical impact of mtDNA mutations in cancer. However, the mechanistic details of this effect, alongside fundamental questions of the role mtDNA mutations play in cancer initiation and progression remain unaddressed, with a lack of experimental mtDNA model systems available to investigate this further. To date, the field has relied on mouse models that undergo random and continuous mutagenesis of mtDNA, which do not recapitulate the disease state. Applying my expertise at the intersection of mitochondrial and cancer biology with my highly specialist, proven track record in mtDNA genome engineering, I propose creation of models and methods to advance understanding of mitochondrial genetics in cancer, addressing the present discovery-limiting technical shortfall. Taking colorectal cancer as an initial paradigm, I will: i) use advanced mtDNA manipulation tools of my own invention to create new state-of-the-art mouse models of colorectal cancer with manipulable levels of a cancer-relevant mtDNA mutation (WP1); ii) apply and modify recently developed mtDNA mutagenesis methods to create new state-of-the-art models of colorectal cancer bearing mtDNA mutations analogous to those I identified in human disease (WP2); iii) develop methods to revolutionise genetic manipulation of mtDNA, permitting creation of any mtDNA variant - well beyond the present state-of-the-art (WP3). Through this proposal, I will answer fundamental questions of how colorectal cancer is modified by mtDNA mutational state (Aim 1) while creating broadly applicable mtDNA tools and models to power further research into cancer far beyond present technical limits (Aim 2).

线粒体 DNA 突变存在于约 60% 的肿瘤中，但在癌症生物学中长期以来一直被忽视。我的实验室最近的突破性工作已确定 mtDNA 突变是所有癌症的主要表型修饰因子，结直肠癌中的 mtDNA 突变与寿命的大幅延长有关，这是 mtDNA 突变对癌症的临床影响的第一个有力证据。然而，这种效应的机制细节以及 mtDNA 突变在癌症发生和进展中所起的作用的基本问题仍未得到解决，而且缺乏可用于进一步研究的实验性 mtDNA 模型系统。迄今为止，该领域依赖于进行随机和连续线粒体 DNA 诱变的小鼠模型，这种诱变并不能概括疾病状态。运用我在线粒体和癌症生物学交叉领域的专业知识以及我在 mtDNA 基因组工程方面高度专业且经过验证的记录，我建议创建模型和方法来促进对癌症线粒体遗传学的理解，解决目前限制发现的技术缺陷。以结直肠癌为初始范例，我将： i) 使用我自己发明的先进 mtDNA 操作工具创建新的最先进的结直肠癌小鼠模型，并具有可操作水平的癌症相关 mtDNA 突变 (WP1)； ii) 应用和修改最近开发的 mtDNA 诱变方法，以创建新的最先进的结直肠癌模型，该模型带有类似于我在人类疾病中发现的 mtDNA 突变（WP2）； iii) 开发彻底改变 mtDNA 遗传操作的方法，允许创建任何 mtDNA 变体 - 远远超出目前的最先进技术 (WP3)。通过这个提案，我将回答 mtDNA 突变状态如何改变结直肠癌的基本问题（目标 1），同时创建广泛适用的 mtDNA 工具和模型，以推动远远超出目前技术限制的癌症进一步研究（目标 2）。