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

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特征，但串扰 这些过程之间的关系还没有被很好地理解。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这两个细胞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新陈代谢状态 支持细胞增殖和防止细胞死亡。这伴随着细胞氧化还原状态的改变。 由于增加了可促进氧化应激和基因组不稳定的活性氧的产生 (核和线粒体DNA、mtDNA)。同样，线粒体的呼吸能力也会降低， ROS产生的增加和基因组的不稳定是正常衰老过程的特征。因为衰老是一种 大多数成人癌症的主要危险因素，该计划的项目1的主要前提是与年龄相关的变化 在线粒体动力学中，功能和信号是癌症随年龄增长的易感性的基础。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，线粒体DNA介导的炎症通路是衰老和年龄相关癌症启动的关键特征。我们 还假设一种新形式的适应性细胞信号，称为“氧化有丝分裂兴奋”，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是确定 年龄相关性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作用 到了肝癌。目的2确定线粒体DNA-cGAS-Sting通路在肝脏衰老和衰老中的作用。 依赖型肝癌易感性。而且，目标3是测试氧化有丝分裂作为对肝脏的干预作用 衰老和肝癌。为了实现这些目标，我们将结合使用创新的鼠标模型 我们可以产生特定的基因敲除或在不同的年龄引发肝癌。此外，我们还可以 通过可诱导的和可逆的击倒线粒体抗氧化酶来诱导有丝分裂反应， Sod2(iSOD2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免费专业知识和假设，我们将评估 多种表型(基因表达、染色质重塑、免疫细胞渗透和活性、 炎症、线粒体功能障碍和代谢)在正常衰老的肝脏和年龄依赖性的PTEN中 肝癌基因敲除模型。项目1将提供线粒体方面的专业知识，即线粒体DNA介导的 炎症和适应性线粒体应激信号传递给理解年龄的协同努力- 肝癌的依赖性。主要发现将转化为正常的和来自人类的NALFD肝脏样本 不同年龄的人。

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.