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

项目摘要/摘要 癌症相关性疲劳是癌症最令人衰弱、最痛苦、最常被报道的副作用之一。 高达71%的前列腺癌(PC)患者抱怨在放射治疗(RT)期间感到疲劳。 虽然RT治疗后疲劳反应的病因和相关机制仍不清楚，但 候选人最近发现证据表明，MTOR和p70S6K基因表达的变化与 伴随着RT过程中疲劳的变化。这项拟议的研究将探索 生物分子存在于系统水平的mTOR信号通路中，可能会改变现有的症状 与疲劳相关的管理范式，通过提供对mTOR生物学功能的理解 是受监管的，以及如何从监管失调中走出疲惫。这项拟议的研究是由一个 MTOR途径失调和RT相关疲劳的模型。培训计划的设计是为了 在博士后经验的基础上接受必要的培训以成为 独立研究人员，精通基因组学、其他“组学”和与症状相关的生物信息学 科学。一支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)增进对“组学”(即转录组学、表观基因组学)的认识，以及与 症状的机制；(2)在疲劳表型的特征和在 与患者生物学和临床数据的关系；(3)精通生物信息学(通过教学课程和 全面的动手培训)分析转录、表观基因组和蛋白质数据，以及 对研究结果的解释；以及(4)提高科学写作技能，并与 生物行为、症状管理和组学研究领域，将允许在 高影响力、同行评议的期刊，并提交竞争激烈的NIH R系列基金。培训计划是针对 为期36个月，包括六个核心领域：教学；跨学科研讨会；指导；实验室培训； 研究和传播。提出了三个具体目标。目标1：确定mTOR途径和活性- 立体定向椎体后1个月疲劳评分变化与相关基因的研究 对患有PC的男性样本进行放射治疗(SBRT)。目的2：研究表观遗传学与 与疲劳评分变化相关的mTOR通路基因的调节 在患有PC的男性样本中进行SBRT。目标3：确定mTOR信号变化之间的关联 途径和活性相关蛋白与SBRT治疗前、结束和1个月后疲劳评分的变化 拥有个人电脑的男性样本。这项研究确定了一个新的勘探领域，并与NINR战略非常一致 计划呼吁症状科学研究，重点促进个性化医学，通过理解 通过症状科学研究了解疲劳症状的潜在机制。

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.