Mitochondrial Bioenergetic Mechanism of Cancer Related Fatigue

癌症相关疲劳的线粒体生物能机制

• 批准号: 9123678
• 负责人: Chao-Pin Hsiao
• 金额: $ 9.1万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-10 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9123678
• 关键词: Adenosine Triphosphate; Adverse effects; Anemia; Area; Award; Basic Science; Behavioral Research; Biochemistry; Bioenergetics; Biological; Biomedical Research; Cancer Etiology; Cancer Fatigue; Cancer Intervention; Cancer Patient; Cell physiology; Cells; Chronic; Chronic Fatigue Syndrome; Clinical Research; Communication; Complex; Data; Defect; Disease; Distress; Electron Transport; Electron Transport Complex III; Electrons; Extravasation; Family; Fatigue; Functional disorder; Gene Expression; Genes; Goals; Health; Heme; Human; Hydrogen Peroxide; Hydroxyl Radical; Interdisciplinary Study; Intervention; Investigation; Iron; Iron-Sulfur Proteins; Laboratories; Laboratory Procedures; Lead; Link; Literature; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Measures; Mental Depression; Mentored Research Scientist Development Award; Mentorship; Mitochondria; Molecular Biology; Molecular Genetics; Nutraceutical; Outcome; Oxidative Phosphorylation; Oxygen; Patients; Physical activity; Physiological; Production; Prognostic Marker; Proteins; Quality of life; Radiation; Radiation induced damage; Radiation therapy; Reactive Oxygen Species; Reporting; Research; Research Personnel; Research Project Grants; Research Proposals; Respiratory Chain; Rieske iron-sulfur protein; Role; Science; Severities; Sleep; Sleep disturbances; Superoxides; Symptoms; Testing; Time; Training; Translational Research; Up-Regulation; base; career; clinical practice; cognitive function; common symptom; disabling symptom; exhaustion; experience; faculty research; health related quality of life; improved; insight; member; men; mitochondrial metabolism; neutrophil; novel; programs; skills; solute; symptom management; therapy design; uptake

 DESCRIPTION (provided by applicant): The long-term objective of my plan for this award is to develop interventional studies targeting the molecular-genetic mechanisms of cancer-related fatigue identified in my initial study and to determine their role in mitigating symptoms. My career goal is to become an independent investigator, developing and conducting translational research linking insights from basic science, behavioral research, and clinical practice in the area of cancer symptom management. To that end, the K01 award will enable me to obtain essential training in advanced biomedical research, particularly related to bioenergetics. Under the mentorship of experienced research faculty, this will lead to competitive research proposals integrating bench science, clinical practice, and novel interventions, using a molecular-genetics perspective on symptom management in cancer. Specific Training Objectives: Objective 1. Obtain required in-depth understanding in biochemistry, molecular biology, and mitochondrial metabolism. Objective 2. Develop skills in laboratory measurement of mitochondrial bioenergetics. Objective 3. Optimize and tailor standard laboratory procedures to the use of human lymphocytes in order to test proposed hypotheses. Objective 4. Acquire understanding of the relationships among gene expression, mitochondrial bioenergetics, and patient symptom experience (i.e., fatigue). Objective 5. Improve scientific communication skills required to coordinate laboratory investigation and clinical research. Objective 6. Collaborate with senior investigators to gain experience in leading translational and multidisciplinary research projects. The ultimate purpose of this program of research is to develop and test interventions to improve healthrelated quality of life for prostate cancer patients, specifically targeting fatigue-one of te most common and distressing sequelae of localized radiation therapy (XRT) for cancer. Cancer-related fatigue negatively impacts health outcomes, leading to increased depression, impaired cognitive function, increased sleep disturbance, and decreased health-related quality of life. The physiological mechanisms behind fatigue and its increased severity during localized XRT remain unknown. Although many mechanisms have been proposed for cancerrelated fatigue, the elusiveness of its cause presents barriers to effective management. A reduction in the capacity of neutrophil mitochondria to utilize oxygen and synthesize adenosine triphosphate (ATP) has been associated with chronic fatigue syndrome. Based on our preliminary data and the literature, localized radiation induces damage to cellular processes, alters gene expression (downregulated BCS1L and upregulated SLC25A37), and is accompanied by decreased BCS1L protein and increased mitoferrin-1 protein. Our primary hypothesis is that decreased BCS1L leads to a defect in complex III assembly and activity, causes impaired oxidative phosphorylation (OXPHOS), and results in decreased ATP production that contributes to the fatigue suffered by cancer patients receiving localized XRT. Moreover, the defect in complex III iron-sulfur protein leads to increased electron leakage from complex III and increased production of superoxide. Our hypothesis provides a mechanism for impaired ATP production as a major consequence of XRT that leads to debilitating radiation-induced fatigue. Furthermore, increased reactive oxygen species (ROS) exacerbates the mitochondrial and cellular damage, adding to the pathophysiology of cancer-related fatigue. Specific Research Aims: Aim 1: To quantify the expression of BCS1L and SLC25A37 associated with changes of BCS1L and SLC25A37 protein in lymphocytes from prostate cancer patients with XRT, compared to prostate cancer patients undergoing active surveillance (AS), at baseline, midpoint, and endpoint. Aim 2: To determine mitochondrial bioenergetics profile for prostate cancer patients with XRT compared to those for prostate cancer patients under AS, at baseline, midpoint, and endpoint. 2a. Determine the rate of mitochondrial OXPHOS, especially complex III. 2b. Measure the activity of electron transport chain (ETC) complexes, especially complex III. 2c. Determine the content of ETC complexes, especially complex III. 2d. Measure the amount of ATP and ROS production. Aim 3: To determine the associations among changes in fatigue, changes in the expression of BCS1L and SLC25A37, and changes in the mitochondrial bioenergetics of prostate cancer patients with XRT and AS. 3a. Measure the severity of fatigue at baseline, midpoint, and endpoint for XRT and AS groups. 3b. Determine the associations of changes in fatigue with changes in the expression of BCS1L and SLC25A37, and changes in the mitochondrial bioenergetics over time in XRT and AS groups.

 描述（由申请人提供）：我获得该奖项的长期目标是开展针对我最初研究中发现的癌症相关疲劳的分子遗传机制的介入研究，并确定它们在缓解症状中的作用。我的目标是成为一名独立研究者，开发和开展转化研究，将癌症症状管理领域的基础科学、行为研究和临床实践的见解联系起来。为此，K01 奖将使我能够获得以下方面的基本培训。先进的生物医学研究，特别是相关的在经验丰富的研究人员的指导下，这将产生具有竞争力的研究提案，将实验室科学、临床实践和新颖的干预措施结合起来，利用分子遗传学的视角来治疗癌症的症状。深入了解生物化学、分子生物学和线粒体代谢。 目标 2. 培养线粒体生物能量学的实验室测量技能。 目标 3. 根据人类淋巴细胞的使用优化和定制标准实验室程序，以测试所提出的方案。目标 4. 了解基因表达、线粒体生物能量学和患者症状体验（即疲劳）之间的关系。 目标 5. 提高协调实验室调查和临床研究所需的科学沟通技巧。获得领导转化和多学科研究项目的经验。 该研究计划的最终目的是开发和测试干预措施，以改善前列腺癌患者的健康相关生活质量，特别是针对癌症相关局部放射治疗 (XRT) 最常见和令人痛苦的后遗症之一。疲劳会对健康结果产生负面影响，导致抑郁加剧、认知功能受损、睡眠障碍增加以及与健康相关的生活质量下降。 尽管已经提出了许多机制，但疲劳背后的生理机制及其在局部 XRT 期间的严重程度仍然未知。与癌症相关的疲劳，难以捉摸根据我们的初步数据和文献，中性粒细胞线粒体利用氧和合成三磷酸腺苷 (ATP) 的能力下降与慢性疲劳综合征有关，局部辐射会导致细胞损伤。过程，改变基因表达（BCS1L 下调和 SLC25A37 上调），并伴有 BCS1L 蛋白减少和线粒体铁蛋白 1 蛋白增加，我们的主要假设是 BCS1L 减少导致复合物 III 组装和活性的缺陷会导致氧化磷酸化 (OXPHOS) 受损，并导致 ATP 产生减少，从而导致接受局部 XRT 的癌症患者出现疲劳。此外，复合物 III 铁硫蛋白的缺陷会导致电子增加。我们的假设提供了一种导致 ATP 产生受损的机制，这是 XRT 导致衰弱的辐射引起的疲劳的结果。此外，活性氧 (ROS) 的增加会加剧线粒体。和细胞损伤，增加癌症相关疲劳的病理生理学 具体研究目标： 目标 1：与前列腺癌相比，量化与接受 XRT 的前列腺癌患者淋巴细胞中 BCS1L 和 SLC25A37 蛋白的变化相关的 BCS1L 和 SLC25A37 表达。目标 2：确定接受 XRT 治疗的前列腺癌患者与接受主动监测 (AS) 的基线、中点和终点的线粒体生物能学特征。确定 AS 下前列腺癌患者的线粒体 OXPHOS 率，尤其是复合物 III 的活性，尤其是复合物 III。 ETC 复合物的含量，特别是复合物 III 的含量。 目标 3：确定疲劳变化与 BCS1L 表达变化之间的关联。 3a. 测量 XRT 和 AS 组的疲劳程度变化与 SLC25A37 的基线、中点和终点的疲劳程度。 XRT 组和 AS 组中 BCS1L 和 SLC25A37 的表达以及线粒体生物能随时间的变化。