Oncogenic Disruption of Circadian Rhythm and Chronotherapy

昼夜节律的致癌性破坏和计时疗法

基本信息

批准号：
8718410
负责人：
Brian James Altman
金额：
$ 5.51万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8718410
关键词：
Address Apoptosis Apoptotic Binding Binding Sites Biological Biological Assay Boxing Brain Breeding Cancer Cell Growth Cancer cell line Cell Culture Techniques Cell Death Cell Line Cell Survival Cells Cellular Stress Chronotherapy Circadian Rhythms Conduct Clinical Trials Data Defect Doctor of Philosophy Educational process of instructing Effectiveness Eukaryota Feedback Future Gene Expression Generations Genes Genetic Goals Growth Growth and Development function Hematopoietic Neoplasms Heme Hormones Hour Human Knowledge Light Link Liver Liver neoplasms Luciferases MYC gene Malignant Neoplasms Malignant neoplasm of liver Mammals Manuscripts Measures Mentorship Messenger RNA Metabolic Metabolic Pathway Metabolism Modeling Molecular Monitor Mouse Cell Line Mus Neurons Normal tissue morphology Oncogene Proteins Oncogenes Oncogenic Oncologist Output Pathway interactions Pennsylvania Peripheral Pharmaceutical Preparations Physiological Processes Play Preparation Process Protein Analysis Proteins Regulator Genes Research Research Design Research Personnel Role Sampling Series Solid Neoplasm Techniques The Cancer Genome Atlas Therapeutic Time Tissues Toxic effect Training Tumor Biology Tumor Cell Line Tumor Tissue Universities Xenograft Model Xenograft procedure base c-myc Genes cancer cell cancer therapy career cell growth circadian pacemaker experience genetic analysis in vivo killings lipid biosynthesis mouse model neoplastic cell novel overexpression pro-apoptotic protein professor promoter public health relevance responsible research conduct skills small hairpin RNA symposium transcription factor treatment strategy tumor tumor growth tumor metabolism tumor xenograft tumorigenesis

项目摘要

Project Summary Long Term Goals: The first objective of this proposal is to identify Myc as a disrupter of circadian rhythm in cancer and explore the implications of this finding for tumor cell growth and the development of new therapy approaches. The second objective is to train Brian Altman, PhD under the mentorship of Dr. Chi Dang at the University of Pennsylvania. Brian will be trained in the fields of cancer metabolism and circadian rhythm through acquisition of new research skills, presentations, discussions with labmates and professors, seminars on responsible research conduct, teaching experience, attendance at conferences, and preparation of manuscripts. These will prepare Brian to transition to a career as an independent academic investigator. Background: Circadian rhythms in mammals are 24 hour cycles regulated by a series of molecular feedback loops. While many cancers have disrupted circadian rhythms, there is currently no molecular basis to identify which cancers have altered or absent rhythms, and the implications of disrupted circadian rhythm on cancer cell growth and survival are not well understood. Identifying an oncogene as being associated with circadian disruption would greatly aid in developing future strategies to target these cancers with chronotherapy, or timed administration of cancer treatment to increase effectiveness and reduce toxicity. Myc is an oncogenic transcription factor translocated or amplified in a variety of blood cancers and solid tumors. We have already shown that Myc specifically disrupts circadian rhythm in cancer cell cultures by binding to the same promoters used by circadian-associated proteins and altering circadian gene expression. Therefore, we hypothesize that circadian rhythms in cancers are disrupted by oncogenic overexpression of Myc, that this disruption provides a specific growth advantage to cells, and that we can take advantage of this pathway to treat cancers in a chronotherapeutic manner by specifically targeting the apoptotic pathway. Specific Aims / Study Design: (1) To determine the effect of Myc overexpression on circadian rhythm in mice. (2) To study the role the novel Myc target Rev-erb¿ on tumor cell and xenograft growth. (3) To study the importance of oscillation of apoptotic genes and pharmacologically target the apoptotic pathway in a circadian-dependent manner. To carry out these aims, circadian gene expression and oscillation will be measured in a Myc-driven mouse model of liver cancer compared to normal liver tissue by real-time luminescent circadian monitoring. Next, I will use cell lines representing at least three kinds of cancer as well as xenografts to study the role of upregulated Rev-erb¿ in Myc driven cancers by looking at cell / tumor growth, alterations in gene expression, and specific metabolic pathways that Rev-erb¿ controls. Finally, I will study oscillation of the apoptotic pathway using genetic and protein analysis in tumor cell lines and mouse tumors as well as a functional sensitivity assay to help me determine how we can best use Myc-disruption of circadian rhythm to time specific therapy to tumors based on oscillating sensitivity to apoptosis.

项目概要长期目标：该提案的第一个目标是将 Myc 确定为昼夜节律扰乱者癌症节律，并探讨这一发现对肿瘤细胞生长和新细胞开发的影响第二个目标是在 Chi Dang 博士的指导下培养 Brian Altman 博士。布莱恩将在宾夕法尼亚大学接受癌症代谢和昼夜节律领域的培训。通过获得新的研究技能、演讲、与实验室伙伴和教授的讨论、研讨会负责任的研究行为、教学经验、参加会议和准备这些手稿将为布莱恩做好过渡到独立学术研究者的职业生涯的准备。背景：哺乳动物的昼夜节律是由一系列分子调节的24小时周期。虽然许多癌症扰乱了昼夜节律，但目前还没有分子基础。确定哪些癌症的节律已改变或缺失，以及昼夜节律紊乱的影响对癌细胞生长和存活的影响尚不清楚。昼夜节律紊乱将极大地有助于制定未来针对这些癌症的策略时间疗法，或定时施用癌症治疗以提高疗效并减少 Myc 毒性。是一种在多种血癌和实体瘤中易位或扩增的致癌转录因子。我们已经证明，Myc 通过与昼夜节律相关蛋白使用相同的启动子并改变昼夜节律基因表达。癌症中的昼夜节律被 Myc 致癌过度表达所扰乱，这破坏为细胞提供了特定的生长优势，我们可以利用这种途径通过专门针对细胞凋亡途径以时间治疗方式治疗癌症。具体目标/研究设计：（1）确定Myc过度表达对昼夜节律的影响 (2) 研究新的 Myc 靶点 Rev-erb¿ (3)研究肿瘤细胞和异种移植物的生长。凋亡基因振荡和药理学靶向凋亡途径的重要性为了实现这些目标，昼夜节律基因的表达和振荡将受到影响。在 Myc 驱动的肝癌小鼠模型中与正常肝组织进行实时比较接下来，我还将使用代表至少三种癌症的细胞系。作为异种移植物来研究上调 Rev-erb 的作用¿通过观察细胞/肿瘤来研究 Myc 驱动的癌症 Rev-erb¿ 的生长、基因表达的改变和特定代谢途径最后我会控制。利用肿瘤细胞系和小鼠的遗传和蛋白质分析研究细胞凋亡途径的振荡肿瘤以及功能检测灵敏度来帮助我确定如何最好地利用 Myc 破坏昼夜节律根据对细胞凋亡的振荡敏感性来确定肿瘤的特异性治疗时间。