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

mTOR 通路在放射治疗相关疲劳中的多组学评估

• 批准号: 10282354
• 负责人: Velda Janet Gonzalez-Mercado
• 金额: $ 16.71万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10282354
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Acute; Address; Area; Bioinformatics; Biological; Biological Assay; Biological Process; Blood specimen; Cancer Patient; Candidate Disease Gene; Clinical Data; Collaborations; Complex; DNA Methylation; DNA methylation profiling; Data Analyses; Development; Distress; Enzyme-Linked Immunosorbent Assay; Etiology; Evaluation; Event; Expenditure; FRAP1 gene; Fatigue; Gene Expression; Gene Proteins; Genes; Genetic; Genetic Markers; Genomics; Goals; Grant; Homeostasis; Incidence; Inflammation; Intervention; Journals; Knowledge; Lead; Literature; Malignant Neoplasms; Malignant neoplasm of prostate; Mentors; Mentorship; Methods; Mitochondria; Modeling; Molecular; Molecular Target; Oxidative Stress; Pathway interactions; Patients; Peer Review; Performance; Phenotype; Phosphorylation; Plasma; Population; Postdoctoral Fellow; Productivity; Prostate Cancer therapy; Proteins; Proto-Oncogene Proteins c-akt; Publications; Radiation therapy; Regimen; Reporting; Research; Research Personnel; Research Proposals; Sampling; Science; Scientist; Series; Sirolimus; Strategic Planning; Symptoms; System; TSC1 gene; TSC1/2 gene; Training; United States National Institutes of Health; Whole Blood; Work; Writing; adenylate kinase; base; biobehavior; cancer therapy; care episode; career; cell growth; clinically significant; design; differential expression; disabling symptom; economic implication; effective intervention; effective therapy; energy balance; epigenetic marker; epigenetic regulation; epigenomics; experience; improved; innovation; laboratory experience; mTOR Signaling Pathway; men; mitochondrial dysfunction; mortality; multiple omics; novel; patient oriented research; personalized medicine; prevent; prognostic; prostate radiotherapy; protein expression; radiation response; research data dissemination; side effect; skills; symptom management; symptom science; therapeutic target; transcriptome sequencing; transcriptomics

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.

项目摘要/摘要 癌症相关的疲劳是癌症最令人衰弱，令人沮丧和常见的副作用之一 治疗，多达71％的前列腺癌（PC）患者在放射治疗期间抱怨疲劳（RT）。 尽管对RT治疗的疲劳反应的病因和相关机制仍然难以捉摸，但 候选人最近发现证据表明MTOR和P70S6K的基因表达变化均相关 随着RT的疲劳变化。拟议的研究将探讨 MTOR信号通路中存在的生物分子在系统级别可能会改变现有症状 管理范式与疲劳有关，通过对MTOR生物学功能的方式提供理解 受调节以及疲劳如何从其失调中出现。拟议的研究由 MTOR途径和RT相关疲劳的失调模型。培训计划旨在允许 候选人以她的博士后经验来接受必要的培训，以成为 独立研究者，熟练于与症状有关的基因组学，其他“法律”和生物信息学 科学。一支经验丰富的科学家团队将提供职业指导和培训 目的：（1）增强对“ OMICS”的知识（即转录组学，表观基因组学）以及与 症状机制； （2）在表征疲劳表型和中获得更多专业知识 与患者生物学和临床数据有关； （3）达到生物信息学水平（通过教学课程和 全面的动手培训）在转录组，表观基因组和蛋白质数据的分析中 对发现的解释； （4）提高科学写作技巧，并与专家建立合作 生物行为，症状管理和OMIC研究领域，将成功出版 高影响力，经过同行评审的期刊以及提交竞争性的NIH R系列赠款。培训计划是 36个月，包括六个核心领域：教学；跨学科的半手；资；实验室培训； 研究;和传播。提出了3个具体目标。 AIM 1：确定MTOR途径和活动 - 与立体定向物体前，末端和1个月的疲劳评分变化相关的相关基因 PC男性样本中的放射疗法（SBRT）。目标2：研究表观遗传学之间的关系 调节MTOR途径基因与疲劳得分的变化相关的MTOR途径基因。 SBRT在有PC的男性样本中。 AIM 3：确定MTOR信号变化之间的关联 途径和与活动相关的蛋白质随着SBRT的前，末端和1个月的疲劳评分变化而变化。 用PC的男性样本。这项研究确定了一个新的探索领域，并与Ninr策略很好地结合 计划呼吁对SYM科学进行研究，重点是促进个性化医学，通过理解 通过症状科学研究来疲劳症状的基础机制。