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 在这些过程之间尚不清楚。线粒体是复杂的，动态的细胞器 细胞能量代谢，氧化还原平衡和调节两个细胞的临界信号通路的联系 生理和细胞死亡。在癌细胞中，线粒体通过许多方式重塑以促进代谢状态 支持细胞增殖并预防细胞死亡。这是通过细胞氧化还原状态的变化来实现的 由于活性氧的产生增加，可以促进氧化应激和基因组不稳定性 （核和线粒体DNA，mtDNA）。同样，线粒体呼吸能力降低， ROS产生增加，基因组不稳定性是正常衰老过程的标志。由于衰老是 大多数成人癌症的主要危险因素，该计划1的主要前提是与年龄有关的变化 在线粒体动力学中，功能和信号传导与衰老的癌症敏感性基础。此外，基于 在我们的初步和发布的结果上，我们建议，除了指示线粒体变化外 上面，mtDNA介导的炎症途径是衰老和与年龄有关的癌症开始的关键特征。我们 还假设一种新型的自适应细胞信号传导形式称为“氧化有丝分裂型”，将预防或 延迟与年龄有关的肝功能障碍和癌症倡议。项目1具有三个特定目标。目标1是确定 与年龄有关的线粒体功能障碍在mtDNA介导的炎症信号及其贡献中的作用 肝癌。 AIM 2是确定mtDNA-CGAS圣途径对肝脏衰老和年龄的贡献 依赖肝癌的敏感性。并且，AIM 3是测试氧化有丝分解作为肝脏的干预 衰老和肝癌。为了实现这些目标，我们将使用创新鼠标模型的组合 我们可以在不同年龄产生特定的基因敲除或启动肝癌。此外，我们可以 通过诱导和可逆的有丝热抗氧化剂酶诱导有线摩型反应， SOD2（ISOD2小鼠）。最后，作为该计划中所有四个实验室共同努力的一部分，这些实验室有不同，但是 关于炎症在衰老和癌症中的作用的免费专业知识和假设，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， 正常衰老肝和年龄依赖性PTEN中的炎症，线粒体功能障碍和代谢） 肝癌的敲除模型。项目1将在MTDNA介导的线粒体中贡献专业知识 炎症和适应性线粒体应力信号传导，以了解年龄 肝癌的依赖性。主要发现将转化为正常的和NALFD的肝样本 不同的年龄。