Investigating microRNA miR-34a in lung cancer development and therapy

研究 microRNA miR-34a 在肺癌发展和治疗中的作用

• 批准号: 8901573
• 负责人: Wen Xue
• 金额: $ 24.9万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8901573
• 关键词: Area; Award; Bioinformatics; Biological; Biological Process; Biology; Cancer Model; Cancer Prognosis; Cell Aging; Cell Proliferation; Cell Survival; Cells; Collaborations; Communities; Data; Data Set; Databases; Development; Doxycycline; Educational workshop; Environment; Family; Fostering; Foundations; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Goals; Human; Institutes; Intention; Laboratories; Lung; Lung Neoplasms; Maintenance; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Mentors; MicroRNAs; Modeling; Molecular; Monitor; Mouse Cell Line; Mus; NF-kappa B; Nanotechnology; Pathway interactions; Patients; Phenotype; Play; Postdoctoral Fellow; Protein p53; Publishing; Recruitment Activity; Research; Research Project Grants; Sampling; Seeds; Shapes; Small Interfering RNA; Solid; Staging; Students; System; Technology; Therapeutic Agents; Therapeutic Effect; Training; Treatment Efficacy; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor Volume; Untranslated Regions; Work; abstracting; anticancer research; cancer cell; cancer gene expression; cancer therapy; career; experience; human cancer mouse model; in vivo; in vivo Model; inhibitor/antagonist; interest; medical schools; molecular phenotype; mouse model; nanomaterials; nanoparticle; neoplastic cell; novel; novel strategies; programs; research study; restoration; skills; small hairpin RNA; therapy development; tumor; tumor initiation; tumor progression; undergraduate student

Project Summary/Abstract My research is focused on elucidating the cellular and molecular mechanisms that microRNAs play in cancer. microRNA (miRNA) molecules have emerged as important regulators of many biological processes, including cancer. It is known that many tumor suppressor miRNAs are lowly-expressed in cancer. However, the ability of these miRNAs to restrain tumor progression and whether miRNAs can be therapeutically delivered to treat cancer is not well established in in vivo models. The project proposed within this K99/R00 award outlines the creation and implementation of novel conditional miRNA expression system, nano-particle delivery system, and miRNA target identification pipelines that allow studying microRNA in mouse and human cancer models. The research proposed within this application has been shaped by my experiences studying p53 tumor- suppressor gene restoration, identifying tumor suppressors in liver cancer, performing in vivo shRNA screen, and by my recent efforts to elucidate the therapeutic effects of NF-kB inhibitors in lung cancer. These research projects solidified my interests in pursuing a career studying the fundamental biology of tumor suppressor miRNA in human cancer progression and therapy because miRNAs like miR-34 are emerging mediators of important tumor suppressive pathways. The systems that we propose herein utilize autochthonous mouse models and genetically defined human cancer cells. This study will integrate genetics, bioinformatics and translational nano-technology to study miR-34's function in lung cancer development and evaluate miR-34 family as a potential therapeutic agent for lung cancer. The facilities at the Koch Institute at MIT, and the expertise that my mentor, Dr. Jacks, can provide will be invaluable for successful implementation of this project. The goals of these experiments outlined within are: · Elucidating the mechanisms by which miR-34a inhibits lung tumor progression · Develop nano-technology to systematically deliver miR-34a in mouse and human lung tumor models · Identify and validate novel miR-34a target genes relevant to human lung cancer The research environment in the Jacks Laboratory, MIT, and the surrounding area offers unmatched opportunities for scientific discussion, collaboration, and training. Currently, I supervise an undergraduate student and a technical assistant that work directly with me on experiments pertaining to my research. This is an incredible experience that will endow me with many of the necessary skills to manage an independent laboratory. The scientific community at MIT, the Broad Institute, and Harvard Medical School offers countless seminars and workshops that will continue to foster my scientific development. My immediate goals are to develop the research platform described in this application and to demonstrate its potential to uncover molecular and cellular mechanisms of miR-34a and other tumor suppressor miRNAs. It is my intention to start an independent research program that will capitalize on these in vivo systems by studying tumor-suppressor miRNAs in a variety of tumor models. For the long-term, I am confident that these experiments will provide a solid foundation on which my research program can be built upon. I look forward to educating and recruiting students and postdocs that share my passion for cancer research.

项目总结/摘要 我的研究重点是阐明microRNA在细胞和分子机制中的作用。 癌微小RNA（miRNA）分子已经成为许多生物过程的重要调节剂， 包括癌症已知许多肿瘤抑制miRNA在癌症中低表达。然而，在这方面， 这些miRNAs抑制肿瘤进展的能力以及miRNAs是否可以在治疗上 在体内模型中没有很好地建立递送以治疗癌症的方法。本K99/R 00中建议的项目 该奖项概述了新的条件性miRNA表达系统，纳米颗粒， 递送系统和miRNA靶向鉴定管道，允许在小鼠和人类中研究microRNA 癌症模型。 本申请中提出的研究是由我研究p53肿瘤的经验形成的- 抑制基因修复，肝癌中肿瘤抑制基因的鉴定，体内shRNA筛选， 以及我最近致力于阐明NF-kB抑制剂在肺癌中的治疗作用。这些研究 项目巩固了我的兴趣，追求职业生涯研究肿瘤抑制的基础生物学 miRNA在人类癌症进展和治疗中的作用，因为像miR-34这样的miRNA是新出现的 重要的肿瘤抑制途径。我们在此提出的系统利用本地小鼠 模型和基因定义的人类癌细胞。这项研究将整合遗传学，生物信息学和 翻译纳米技术研究miR-34在肺癌发生中的功能并评估miR-34 家族作为肺癌的潜在治疗剂。麻省理工学院科赫研究所的设施， 我的导师杰克斯博士所能提供的专业知识对于成功实施这一计划将是无价的。 项目 其中概述的这些实验的目标是： ·阐明miR-34 a抑制肺肿瘤进展的机制 ·开发纳米技术，在小鼠和人类肺肿瘤中系统地递送miR-34 a 模型 ·识别和验证与人类肺癌相关的新miR-34 a靶基因 在杰克实验室，麻省理工学院和周边地区的研究环境提供了无与伦比的 科学讨论、合作和培训的机会。目前，我指导一个本科生 学生和一个技术助理直接与我一起进行与我的研究有关的实验。这是 一个令人难以置信的经验，将赋予我许多必要的技能，以管理一个独立的 实验室麻省理工学院、布罗德研究所和哈佛医学院的科学界提供了无数 研讨会和讲习班，将继续促进我的科学发展。 我的近期目标是开发本申请中描述的研究平台， 证明了其揭示miR-34 a和其他肿瘤的分子和细胞机制的潜力 抑制性miRNAs。我打算启动一个独立的研究项目， 通过在各种肿瘤模型中研究肿瘤抑制miRNAs，从长远来看，我 我相信，这些实验将为我的研究计划奠定坚实的基础 上。我期待着教育和招募学生和博士后分享我对癌症的热情 research.