The Metabolic Basis of Cancer-Related Fatigue

项目摘要-癌症相关的疲劳是最常见和最具破坏性的症状之一 被病人。它通常在诊断时出现，在整个治疗过程中恶化，并在 在相当大比例的患者中停止治疗。导致疲劳的具体机制 在很大程度上仍然不为人知。因此，目前还没有针对疲劳的机制指导疗法，而且主要的 对报告严重疲劳的患者的方法是教育和咨询疲劳的自我管理。 虽然能量守恒是疲劳管理中的一项重要战略，但 与癌症相关的疲劳源于能量代谢的改变，尚未得到检查。现在 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 肿瘤及其可能相关的炎症对机体施加的过度代谢需求 和.。这种情况导致的相对代谢效率低下会因线粒体而恶化。 外周组织和大脑因化疗和放射治疗而出现的损伤。至 测试我们的假设，我们将使用两个同基因的小鼠癌症模型，这两个模型都对 顺铂和局部照射，一种模仿人乳头瘤病毒相关头部的非炎性模型 宫颈癌，以及以Lewis肺癌为代表的炎症模型。我们将测量行为 在这两种情况下，由于自愿车轮运行减少和动机行为的改变而导致的疲劳 说明疲劳的激励因素。在目标1中，我们将确定炎症是否与 与肿瘤及其治疗需要传播到大脑的疲劳发展。这将通过以下方式完成 比较干预前外周和脑内炎症与疲劳的时间进程 要么通过被动免疫来阻断免疫信号分子，要么耗尽能够 调节外周和大脑的炎症过程。在目标2中，我们将检验假设 癌症和炎症导致的代谢重新编程导致相对能量代谢的状况 因癌症治疗导致的线粒体功能障碍而加重的缺乏症。这将通过以下方式完成 在评估之前确定代谢重新编程和行为疲劳之间的关联 加剧线粒体损伤会加剧疲劳的行为和代谢表型，而 防止线粒体损伤会产生相反的效果。在目标3中，我们将检验以下假设 线粒体和细胞核自身DNA泄漏的胞浆DNA感受器触发了整个过程。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.