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).

MTDNA的突变存在于所有肿瘤的60％中，并且在癌症生物学中长期以来一直被忽略。我实验室的最新开创性工作将mtDNA突变确定为所有癌症中的主要表型模型，而大肠癌中的mtDNA突变与寿命的主要扩展有关，这是MTDNA突变在癌症中的临床影响的第一个强大证据。但是，这种效果的机械细节以及MTDNA突变在癌症开始和进展中起着作用的基本问题，尚未解决，缺乏实验性mtDNA模型系统来进一步研究。迄今为止，该领域依赖于经历mtDNA的随机和连续诱变的小鼠模型，这些模型不会概括疾病状态。在线粒体和癌症生物学与我的高度专家，在MTDNA基因组工程中久经考验的记录中，将我的专业知识应用于相交，我建议创建模型和方法，以促进对癌症中线粒体遗传学的了解，以解决当前发现限制的技术介绍。我将以结直肠癌为初始范式，我将：i）使用我自己发明的先进mtDNA操纵工具来创建新的最先进的结直肠癌的小鼠模型，并具有可操纵的癌症相关的mtDNA突变（WP1）； ii）应用并修改了最近开发的mtDNA诱变方法，以创建与我在人类疾病中发现的那些类似于我在人类疾病中发现的结构直肠癌突变的最新模型（WP2）； iii）开发方法来彻底改变mtDNA的遗传操纵，从而允许创建任何mtDNA变体 - 远远超出了当前的最先进（WP3）。通过该提案，我将回答有关如何通过mtDNA突变状态修改结直肠癌的基本问题（AIM 1），同时创建广泛适用的mtDNA工具和模型，以推动对远远超​​出当前技术限制的进一步研究（AIM 2）。