The Metabolic Basis of Cancer-Related Fatigue

项目摘要-癌症相关的疲劳是最常见的和破坏性的症状之一经历 被病人。它通常在诊断时就存在，在整个治疗过程中持续存在，并在治疗后持续很长时间。 大部分患者停止治疗。造成疲劳的具体机制 仍然在很大程度上未知。因此，没有机制指导的疲劳疗法， 报告严重疲劳的患者的方法是自我管理疲劳的教育和咨询。 虽然能量守恒是疲劳管理的重要策略，但 癌症相关的疲劳源于能量代谢的改变还没有被研究。本 项目填补了这一空白。我们的工作假设是，癌症相关的疲劳是行为的结果， 肿瘤及其可能相关的炎症对生物体施加的过度代谢需求 以.由这种情况导致的相对代谢效率低下被线粒体破坏而恶化。 对化疗和放疗作出反应而在外周组织和大脑中发展的损伤。到 为了验证我们的假设，我们将使用两种同基因小鼠癌症模型，它们都对以下组合有反应： 顺铂和局部照射，模拟人乳头瘤病毒相关头部的非炎症模型， 颈癌和以刘易斯肺癌为代表的炎性模型。我们将测量行为 疲劳在这两种情况下减少自愿车轮运行和改变动机行为， 解释疲劳的动机成分。在目标1中，我们将确定炎症是否与 肿瘤和它的治疗需要传播到大脑疲劳发展。会来做这项工作 将外周和大脑中的炎症的时间过程与干预前的疲劳进行比较 通过被动免疫来阻断免疫信号分子，或者耗尽先天免疫细胞， 介导周围和大脑中的炎症过程。在目标2中，我们将检验以下假设： 由癌症和炎症引起的代谢重编程导致相对能量代谢的状况 癌症治疗引起的线粒体功能障碍加剧了这种缺陷。会来做这项工作 确定代谢重编程和行为疲劳之间的关联，然后评估是否 加剧线粒体损伤会加剧疲劳的行为和代谢表型， 防止线粒体损伤具有相反的效果。在目标3中，我们将检验以下假设： 细胞质DNA传感器通过自身DNA从线粒体和细胞核泄漏触发整个过程。这 研究应该有助于理解和治疗癌症相关的疲劳。

Project Summary – Cancer-related fatigue is one of the most common and disruptive symptoms experienced by patients. It is often present at the time of diagnosis, worsens throughout treatment, and persists well after the cessation of treatment in a significant proportion of patients. The specific mechanisms responsible for fatigue remain largely unknown. Consequently, there are no mechanism-guided therapies for fatigue and the primary approach to patients reporting severe fatigue is education and counseling in the self-management of fatigue. Although conservation of energy is an important strategy in the management of fatigue, the possibility that cancer-related fatigue originates from alterations in energy metabolism has not been examined. The present project fills this void. Our working hypothesis is that cancer-related fatigue is the behavioral consequence of the excess metabolic demand imposed on the organism by the tumor and the inflammation it is possibly associated with. The relative metabolic inefficiency that results from this condition is worsened by the mitochondrial impairment that develops in peripheral tissues and the brain in response to chemotherapy and radiotherapy. To test our hypothesis, we will use two syngeneic murine models of cancer that both respond to a combination of cisplatin and local irradiation, a non-inflammatory model mimicking human papilloma virus-related head and neck cancer, and an inflammatory model represented by Lewis lung carcinoma. We will measure behavioral fatigue in both conditions by decreased voluntary wheel running and alterations in motivated behavior to account for the motivational component of fatigue. In Aim 1, we will determine whether inflammation associated with the tumor and its treatment needs to propagate to the brain for fatigue to develop. This will be done by comparing the time course of inflammation at the periphery and in the brain to that of fatigue before intervening to either block immune signaling molecules by passive immunization or deplete the innate immune cells that mediate the inflammatory process at the periphery and in the brain. In Aim 2, we will test the hypothesis that metabolic reprogramming by cancer and inflammation leads to a condition of relative energy metabolism deficiency that is exacerbated by cancer therapy-induced mitochondrial dysfunction. This will be done by determining the association between metabolic reprogramming and behavioral fatigue before assessing whether intensifying mitochondrial damage exacerbates the behavioral and metabolic phenotypes of fatigue while preventing mitochondrial damage has the reverse effect. In Aim 3, we will test the hypothesis that activation of cytosol DNA sensors by self DNA leaking from mitochondria and cell nuclei triggers this whole process. This research should help understand and treat cancer-related fatigue.