Multi-omic Evaluation of the mTOR pathway in Radiotherapy-Related Fatigue

项目概要/摘要 癌症相关的疲劳是最衰弱，痛苦，和常见的癌症副作用之一 高达71%的前列腺癌（PC）患者在放射治疗（RT）期间抱怨疲劳。 虽然对RT治疗的疲劳反应的病因学和相关机制仍然难以捉摸， 候选人最近发现的证据表明，MTOR和p70 S6 K基因表达的变化与 与RT期间疲劳的变化。拟议的研究将探讨网络之间的相互作用， 生物分子存在于系统水平的mTOR信号通路中，这可能会改变现有的症状 管理范式，因为它涉及疲劳，通过提供如何mTOR生物功能的理解， 以及疲劳如何从其失调中出现。该研究由一个 mTOR通路失调和RT相关疲劳的模型。培训计划的目的是 候选人建立在她的博士后经验，接受必要的培训，成为一个 独立研究者，精通基因组学、其他“组学”和与症状相关的生物信息学 科学一个经验丰富的科学家团队将提供以下职业指导和培训 目标：（1）提高对“组学”的认识（即，转录组学，表观基因组学），以及与 症状的机制;（2）获得疲劳表型表征和 与患者生物学和临床数据的关系;（3）达到生物信息学水平（通过教学课程和 全面的实践培训）在转录组学，表观基因组学和蛋白质数据的分析，以及 研究结果的解释;（4）提高科学写作技能，并与专家建立合作关系。 生物行为，症状管理和组学研究领域，将允许成功的出版物， 高影响力，同行评审的期刊，并提交竞争性NIH R系列资助。培训计划是为了 为期36个月，包括六个核心领域：教学;跨学科研讨会;导师制;实验室培训; 研究;传播。提出了三个具体目标。目的1：确定mTOR通路和活性- 与立体定向体治疗前、治疗结束时和治疗后1个月疲劳评分变化相关的相关基因 放射治疗（SBRT）在PC的男性样本。目的2：研究表观遗传学之间的关系 mTOR通路基因的调节与术前、术后和术后1个月的疲劳评分变化相关 SBRT在PC男性样本中。目的3：确定mTOR信号传导变化之间的关联 在SBRT治疗前、治疗结束后和治疗后1个月， PC男性样本。这项研究确定了一个新的探索领域，并与NINR战略保持良好一致 计划呼吁研究症状科学，重点是促进个性化医疗，通过了解 通过症状学研究探讨疲劳症状的发生机制。

PROJECT SUMMARY/ABSTRACT Cancer-related fatigue is one of the most debilitating, distressing, and commonly reported side effects of cancer treatment, with up to 71% of prostate cancer (PC) patients complaining of fatigue during radiation therapy (RT). While the etiology and associated mechanisms of the fatigue responses to RT treatment remain elusive, the candidate recently found evidence that changes in gene expression of both MTOR and p70S6K were associated with changes in fatigue during RT. The proposed study will explore the network of interactions among the biomolecules present in mTOR signaling pathways at the systems level, which could shift existing symptom management paradigm as it relates to fatigue by offering an understanding of how the mTOR biological functions are regulated and how the fatigue may emerge from its dysregulation. The proposed research is guided by a model of dysregulation of the mTOR pathway and RT-related fatigue. The training plan was designed to allow the candidate to build on her post-doctoral experience to receive the necessary training to become an independent investigator, proficient in genomics, other “omics”, and bioinformatics as they relate to symptom science. An experienced team of scientists will provide career mentoring and training with the following objectives: (1) enhance knowledge of “omics” (i.e., transcriptomics, epigenomics), and the science related to mechanisms of symptoms; (2) gain additional expertise in the characterization of fatigue phenotypes and in relation to patient biological and clinical data; (3) attain bioinformatics proficiency (via didactic coursework and comprehensive hands-on training) in the analysis of transcriptomic, epigenomic, and protein data, and interpretation of the findings; and (4) improve scientific writing skills and build collaborations with experts in the fields of bio-behavioral, symptom management, and omic research that will allow for successful publications in high-impact, peer-reviewed journals, and submission of competitive NIH R-Series grant. The training plan is for thirty-six months and includes six core areas: didactic; interdisciplinary seminars; mentorship; laboratory training; research; and dissemination. There are 3 specific aims proposed. Aim 1: Identify mTOR pathway and activity- related genes associated with changes in fatigue scores from pre, end, and 1 month after stereotactic body radiation therapy (SBRT) in a sample of men with PC. Aim 2: Investigate the relationships between epigenetic regulation of mTOR pathway genes associated with changes in fatigue scores from pre, end, and 1 month after SBRT in a sample of men with PC. Aim 3: Determine the associations between changes in mTOR signaling pathway and activity-related proteins with changes in fatigue scores from pre, end, and 1 month after SBRT in a sample of men with PC. This study identifies a novel area for exploration and aligns well with the NINR Strategic Plan calling for studies on symptom science with a focus on Promoting Personalized Medicine, by understanding the mechanisms underlying the symptom of fatigue through symptom science research.