Project 1: The role of mitochondrial stress in liver aging and cancer progression and intervention via oxidative mitohormesis

项目1：线粒体应激在肝脏衰老和癌症进展中的作用以及通过氧化线粒体兴奋作用进行干预

• 批准号: 10698104
• 负责人: GERALD SHADEL
• 金额: $ 41.16万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698104
• 关键词: Acceleration; Acute; Address; Adult; Age; Aging; Animals; Antioxidants; Antiviral Response; Binding Proteins; Cancer Intervention; Cancer Model; Cell Death; Cell Proliferation; Cell physiology; Cells; Chemoresistance; Complex; Cytosol; DNA; DNA Repair; Data; Dependence; Development; Embryonic Development; Energy Metabolism; Equilibrium; Functional disorder; Gene Expression; Genes; Genetic; Genomic Instability; High Fat Diet; Human; Inflammation; Inflammatory; Inherited; Interferon Type I; Interferons; Intervention; Kinetics; Knock-out; Knockout Mice; Liver; Liver Dysfunction; Longevity; Malignant Neoplasms; Malignant neoplasm of liver; Mammals; Mediating; Membrane Proteins; Metabolic; Metabolism; Mitochondria; Mitochondrial DNA; Mus; Nuclear; Organelles; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Pathology; Pathway interactions; Phenotype; Predisposition; Process; Production; Proteins; Publishing; Reactive Oxygen Species; Regimen; Risk Factors; Role; SOD2 gene; Sampling; Signal Pathway; Signal Transduction; Specific qualifier value; Stimulator of Interferon Genes; Sting Injury; Stress; Supporting Cell; System; Testing; Time; Tissues; Translating; Viral; Viral Oncogene; Voltage-Dependent Anion Channel; age related; antioxidant enzyme; beta catenin; biological adaptation to stress; cancer cell; cancer initiation; cancer predisposition; chromatin remodeling; immune cell infiltrate; innate immune pathways; innovation; knock-down; knockout gene; liver cancer model; liver cancer prevention; liver inflammation; mitochondrial dysfunction; mitochondrial metabolism; model organism; molecular phenotype; mouse model; multidimensional data; normal aging; novel; pharmacologic; prevent; programs; respiratory; response; tumor progression

PROJECT SUMMARY – PROJECT 1 Mitochondrial dysfunction, oxidative stress and inflammation are hallmarks of aging and cancer, but crosstalk between these processes are not well understood. Mitochondria are complex and dynamic organelles at the nexus of cellular energy metabolism, redox balance, and critical signaling pathways that regulate both cell physiology and cell death. In cancer cells, mitochondria are remodeled in many ways to promote metabolic states that support cell proliferation and prevent cell death. This is accompanied by changes in cellular redox status due to increased reactive oxygen species production that can promote oxidative stress and genomic instability (of both nuclear and mitochondrial DNA, mtDNA). Similarly, reduced mitochondrial respiratory capacity, increased ROS production, and genomic instability are hallmarks of the normal aging process. Since aging is a major risk factor for most adult cancers, the major premise of Project 1 of the program is that age-related changes in mitochondrial dynamics, function and signaling underlie cancer susceptibility with aging. Furthermore, based on our preliminary and published results, we propose that, in addition to the mitochondrial changes indicated above, mtDNA-mediated inflammatory pathways are a key feature of aging and age-related cancer initiation. We also hypothesize that a novel form of adaptive cellular signaling, called “oxidative mitohormesis,” will prevent or delay age-related liver dysfunction and cancer initiation. Project 1 has three specific aims. Aim 1 is to determine the role of age-related mitochondrial dysfunction in mtDNA-mediated inflammatory signaling and its contribution to liver cancer. Aim 2 is to determine the contribution of the mtDNA-cGAS-Sting pathway to liver aging and age- dependent liver cancer susceptibility. And, Aim 3 is to test oxidative mitohormesis as an intervention for liver aging and liver cancer. To accomplish these aims we will use a combination of innovative mouse models in which we can generate specific gene knock-outs or initiate liver cancer at different ages. In addition, we can induce mitohormetic responses by inducible and reversible knock-down of the mitochondrial antioxidant enzyme, SOD2 (iSOD2 mice). Finally, as part of common effort by all four labs in the program, who have different, but complimentary expertise and hypotheses about the role of inflammation in aging and cancer, we will assess a multitude of phenotypes (gene expression, chromatin remodeling, immune cell infiltration and activity, inflammation, mitochondrial dysfunction and metabolism) in normal aging liver and in an age-dependent Pten knock-out model of liver cancer. Project 1 will contribute expertise in mitochondria, mtDNA-mediated inflammation, and adaptive mitochondrial stress signaling to this concerted effort to understand the age- dependence of liver cancer. Key findings will be translated into normal and NALFD liver samples from humans of different ages.

项目摘要-项目1 线粒体功能障碍，氧化应激和炎症是衰老和癌症的标志，但串扰 这些过程之间的关系还没有很好的理解。线粒体是一种复杂的动态细胞器， 细胞能量代谢、氧化还原平衡和调节细胞内和细胞外的关键信号通路之间的联系 生理学和细胞死亡。在癌细胞中，线粒体以多种方式重塑以促进代谢状态 支持细胞增殖并防止细胞死亡。这伴随着细胞氧化还原状态的变化 由于增加的活性氧物质的产生可以促进氧化应激和基因组不稳定性， (of核和线粒体DNA，mtDNA）。同样，线粒体呼吸能力降低， 增加的ROS产生和基因组不稳定性是正常衰老过程的标志。因为衰老是一种 大多数成人癌症的主要危险因素，该计划项目1的主要前提是，与年龄有关的变化 在线粒体动力学中，功能和信号转导是随着年龄增长的癌症易感性的基础。此外，基于 根据我们的初步和发表的结果，我们提出，除了线粒体的变化表明， 如上所述，mtDNA介导的炎性途径是衰老和年龄相关的癌症起始的关键特征。我们 我还假设一种新形式的适应性细胞信号，称为“氧化性有丝分裂”，将防止或 延缓与年龄相关的肝功能障碍和癌症的发生。项目1有三个具体目标。目标1：确定 年龄相关线粒体功能障碍在线粒体DNA介导的炎症信号中的作用及其贡献 到肝癌。目的2是确定mtDNA-cGAS-Sting通路对肝脏衰老和年龄的贡献。 依赖性肝癌易感性目的3是检测氧化有丝分裂作为肝脏干预的可能性。 衰老和肝癌为了实现这些目标，我们将使用创新的小鼠模型组合， 我们可以产生特定的基因敲除或在不同年龄引发肝癌。此外，我们还可以 通过线粒体抗氧化酶的可诱导和可逆敲低来诱导促分裂反应， S 0 D2（iS 0 D2小鼠）。最后，作为项目中所有四个实验室共同努力的一部分，他们有不同的，但 关于炎症在衰老和癌症中的作用的补充专业知识和假设，我们将评估一个 多种表型（基因表达，染色质重塑，免疫细胞浸润和活性， 炎症，线粒体功能障碍和代谢）在正常老化肝脏和年龄依赖性Pten 肝癌基因敲除模型。项目1将在线粒体、mtDNA介导的 炎症，和适应性线粒体应激信号，以这种协调一致的努力，以了解年龄- 肝癌的依赖性。关键发现将转化为人类正常和NALFD肝脏样本 不同的年龄。