Characterization of a microRNA network regulating glioblastoma epigenetics, cell reprogramming and DNA repair

调节胶质母细胞瘤表观遗传学、细胞重编程和 DNA 修复的 microRNA 网络的表征

• 批准号: 9295703
• 负责人: Pier Paolo Peruzzi
• 金额: $ 19.84万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295703
• 关键词: Adult; Affect; Area; Award; Basic Science; Benign; Biological; Biological Process; Biology; Brain Neoplasms; Cell Differentiation process; Cell Maintenance; Cell Survival; Cells; Characteristics; Chromatin; Chronology; Complex; DNA; DNA Damage; DNA Modification Methylases; DNA Repair; DNA Sequence; Data; Down-Regulation; Engineering; Environment; Epigenetic Process; Funding; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Genome; Genotoxic Stress; Glioblastoma; Glioma; Goals; Grant; Histone Deacetylase; Impairment; In Vitro; Institutes; K-Series Research Career Programs; Laboratory Research; Malignant - descriptor; Malignant neoplasm of brain; Mediating; Mentors; Messenger RNA; Methods; MicroRNAs; Neurons; Neurosurgeon; Normal Cell; Oncogenic; PRC1 Protein; Pathway interactions; Pharmaceutical Preparations; Phenotype; Polycomb; Positioning Attribute; Primary Brain Neoplasms; Proteins; Publications; RNA; Radiation; Radiation therapy; Regulation; Regulator Genes; Research; Research Methodology; Research Personnel; Resistance; Role; SECTM1 gene; Scientist; Stem cells; Techniques; Testing; Therapeutic; Training; Training Programs; Transcript; Translations; Tumor Biology; Untranslated RNA; Viral; Work; Writing; antitumor effect; base; career development; cellular targeting; chemotherapy; chromatin modification; combinatorial; conventional therapy; design and construction; epigenetic regulation; experimental study; gene therapy; in vivo; innovation; neurosurgery; novel; novel strategies; overexpression; prevent; public health relevance; relating to nervous system; response; responsible research conduct; screening; stem; temozolomide; trait; transcription factor; tumor

ABSTRACT This K08 Mentored Career Development Award proposal describes a 4 year training program for the candidate, a neurosurgeon-scientist whose long term goal is to become an independent investigator in the field of primary malignant brain tumors, with a particular focus on the relevance of microRNA-mediated interference with GBM biology and survival response to conventional therapies. The basic science expertise earned by the candidate during his graduate studies while a resident in neurosurgery, put him in the ideal position to carry over this research. Previously, the candidate has shown that miR-128, a microRNA preferentially expressed in neurons, has an antitumor effect by targeting multiple GBM proteins involved with stem cell maintenance, as well as resistance to radiation therapy. He now hypothesizes that there are other microRNAs whose abnormal expression in GBM parallels that of miR-128, and thus that multiple microRNAs could work in functional clusters to effectively reprogram GBM cells into neuron-like cells by acting on a multiplicity of proteins with an epigenetic role. He also proposes that this can be harnessed to obtain a major sensitizing effect to radiation and chemotherapy. To test his hypothesis he proposes the following 3 specific aims: 1) to investigate the mechanistic and biological relevance of this observed clustering of several microRNAs in the regulation of multiple epigenetic complexes; 2) to design and construct a viral-based delivery method to re-express multiple microRNAs in GBM cells thus achieving substantial reprogramming of GBM cells into a more benign phenotype; 3) to explore how multiple microRNA re-expression can affect key cellular survival responses implicated in resistance to radiation and temozolomide treatment. This is extremely relevant because GBM is characterized by multiple aberrancies in several oncogenic pathways, which can not be targeted by single drugs, but could be regulated by these microRNAs clusters and their unique ability to simultaneously target multiple proteins fundamental to tumor biology. It is also very innovative, as it proposes a new approach to investigating the role of microRNAs in GBM, and also outlines a feasible method for producing artificial DNA sequences encoding multiple microRNAs that can be used in a gene-therapy setting. The candidate works in an exceptional academic environment, where he has already been able to set up his research laboratory, and will perform his experiments and proposed research under the guidance of Dr Chiocca and Dr Godlewsky as his co-mentors. Also, Dr Ligon, an expert in Neural and GBM stem cells and Dr Haas-Kogan, expert in DNA repair mechanism in brain tumors, will function as advisors for their respective areas of expertise. The candidate has already proven himself to be a dedicated and productive researcher, as demonstrated by his publications, awards, and funding, the last in chronological order being a K12 career development award obtained last year. To further advance his career development, the candidate has outlined his plan for specific hands-on training for mastering different research methodologies, such as comprehensive RNA and protein screening, interpretation of gene transcriptional analysis, and techniques for studying DNA damage and repair. In addition, the candidate will be involved in formal coursework in grant writing and responsible conduct of research.

抽象的 该K08指导的职业发展奖提案描述了一项为期4年的培训计划 候选人，神经外科医生，其长期目标是成为独立研究者 原发性恶性脑肿瘤的领域，特别关注microRNA介导的相关性 干扰GBM生物学和对常规疗法的生存反应。基础科学专业知识 在神经外科居民的研究生学习期间，候选人赢得了他的理想 进行这项研究的位置。以前，候选人表明mir-128，microRNA 在神经元中优先表达的，具有抗肿瘤作用，通过靶向多种与 干细胞维持以及对放射疗法的抗性。他现在假设还有其他 MicroRNA在GBM中的异常表达与miR-128的表达相似，因此多个microRNA 可以在功能簇中起作用，通过作用于A 具有表观遗传作用的蛋白质多样性。他还建议可以利用这一点 对放射和化学疗法的敏感性。为了检验他的假设，他提出以下3个特定的 目的：1）研究该观察到的几个聚类的机械和生物学相关性 在调节多种表观遗传复合物中的microRNA； 2）设计和构建基于病毒的传递 重新表达GBM细胞中多个microRNA的方法，从而实现了GBM的大量重编程 细胞成一个更良性的表型； 3）探索多个microRNA重新表达如何影响钥匙细胞 与辐射和替莫唑胺治疗的抗性有关的生存反应。这是非常相关的 因为GBM的特征是几种致癌途径中的多个畸变，这是不可能的 由单一药物瞄准，但可以由这些microRNA簇及其独特的能力来调节 同时靶向肿瘤生物学基础的多种蛋白质。它也非常创新，因为它提出了 研究microRNA在GBM中的作用的新方法，并概述了一种可行的方法 产生编码可用于基因疗法环境的多个microRNA的人工DNA序列。 候选人在特殊的学术环境中工作，他已经能够建立他的 研究实验室，并将在DR的指导下进行实验和拟议的研究 Chiocca和Godlewsky博士是他的联合委托人。此外，Ligon博士是神经和GBM干细胞的专家，博士 Haas-Kogan是脑肿瘤中DNA修复机制的专家，将充当各自的顾问 专业领域。 候选人已经证明自己是一位敬业和富有成效的研究人员，如 他的出版物，奖项和资金，按时间顺序排列的最后一个是K12职业发展奖 去年获得。 为了进一步推进他的职业发展，候选人概述了他的特定动手培训计划 用于掌握不同的研究方法，例如综合RNA和蛋白质筛选， 基因转录分析的解释以及研究DNA损伤和修复的技术。在 此外，候选人将参与正式课程，以授予写作和负责任的行为 研究。