Mitochondrial Bioenergetic Mechanism of Cancer Related Fatigue

 描述（由申请人提供）：我计划获得该奖项的长期目标是开发针对我初步研究中确定的癌症相关疲劳的分子遗传机制的干预性研究，并确定它们在缓解症状中的作用。我的职业目标是成为一名独立的研究者，开发和进行转化研究，将基础科学，行为研究和癌症症状管理领域的临床实践联系起来。为此，K 01奖将使我能够获得先进的生物医学研究，特别是与生物能量学相关的基本培训。在经验丰富的研究人员的指导下，这将导致竞争性的研究提案，整合实验室科学，临床实践和新的干预措施，使用分子遗传学的角度对癌症症状管理。具体培训目标：目标1。获得所需的深入了解生物化学，分子生物学和线粒体代谢。目标2.培养线粒体生物能量学实验室测量技能。目标3.优化和定制标准实验室程序，以使用人类淋巴细胞，以测试提出的假设。目标4.了解基因表达、线粒体生物能量学和患者症状体验之间的关系（即，疲劳）。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能。目标6.与高级研究人员合作，获得领先的翻译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，特别是针对疲劳-癌症局部放射治疗（XRT）最常见和最令人痛苦的后遗症之一。癌症相关的疲劳对健康结果产生负面影响，导致抑郁症增加，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。疲劳背后的生理机制及其在局部XRT期间严重程度增加仍然未知。尽管已经提出了许多癌症相关疲劳的机制，但其原因的难以捉摸给有效管理带来了障碍。中性粒细胞线粒体利用氧和合成三磷酸腺苷（ATP）的能力降低与慢性疲劳综合征有关。根据我们的初步数据和文献，局部辐射诱导细胞过程损伤，改变基因表达（下调BCS 1 L和上调SLC 25 A37），并伴有BCS 1 L蛋白减少和线粒体铁蛋白-1蛋白增加。我们的主要假设是BCS 1 L减少导致复合物III组装和活性缺陷，导致氧化磷酸化（OXPHOS）受损，并导致ATP产生减少，导致接受局部XRT的癌症患者疲劳。此外，复合物III铁硫蛋白的缺陷导致复合物III的电子泄漏增加和超氧化物的产生增加。我们的假设提供了一种机制，受损的ATP生产的主要后果XRT，导致衰弱的辐射诱导的疲劳。此外，活性氧（ROS）的增加会加剧线粒体和细胞的损伤，加剧癌症相关疲劳的病理生理学。具体研究目标：目标1：与接受主动监测（AS）的前列腺癌患者相比，在基线、中点和终点，定量XRT前列腺癌患者淋巴细胞中与BCS 1 L和SLC 25 A37蛋白变化相关的BCS 1 L和SLC 25 A37表达。目标二：确定基线、中点和终点时XRT治疗前列腺癌患者与AS治疗前列腺癌患者的线粒体生物能量学特征。2a.测定线粒体OXPHOS，特别是复合物III的速率。2b.测量电子传递链（ETC）复合物，特别是复合物III的活性。2c.测定ETC复合物的含量，特别是复合物III。2d.测量ATP和ROS的产生量。目标3：确定XRT和AS前列腺癌患者疲劳变化、BCS 1 L和SLC 25 A37表达变化以及线粒体生物能量学变化之间的相关性。3a.测量XRT和AS组在基线、中点和终点时的疲劳严重程度。3b.确定XRT和AS组中疲劳变化与BCS 1 L和SLC 25 A37表达变化以及线粒体生物能量学随时间变化的相关性。

 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.