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: 8916640
• 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/8916640
• 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.

项目摘要/摘要 我的研究重点是阐明microRNA在中的细胞和分子机制 癌症。 microRNA（miRNA）分子已成为许多生物过程的重要调节剂， 包括癌症。众所周知，许多肿瘤抑制器中的miRNA在癌症中低表达。然而， 这些miRNA限制肿瘤进展的能力以及miRNA是否可以热 用于治疗癌症的治疗模型尚未确定为治疗癌症。该项目在此K99/R00中提出 奖项概述了新型条件miRNA表达系统纳米颗粒的创建和实施 输送系统和miRNA靶标识别管道，允许在小鼠和人类中研究microRNA 癌症模型。 我研究p53肿瘤的经验所提出的研究是由我塑造的。 抑制基因恢复，鉴定肝癌中的肿瘤促进剂，在体内shRNA筛查中进行 通过我最近阐明NF-KB抑制剂在肺癌中的治疗作用的努力。这些研究 项目巩固了我从事研究肿瘤抑制剂基本生物学的职业的兴趣 人类癌症进展和治疗中的miRNA，因为miR-34之类的miRNA是新兴的介体 重要的肿瘤抑制途径。我们在此提出的系统利用自动鼠标 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 转化纳米技术研究miR-34在肺癌开发和评估中的功能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， 我的心理杰克斯博士可以提供的专业知识对于成功实施这将是无价的 项目。 其中概述的这些实验的目标是： ·阐明miR-34a抑制肺肿瘤进展的机制 ·开发纳米技术以系统地传递小鼠和人肺肿瘤中的miR-34a 型号 识别和验证与人肺癌相关的新型miR-34a靶基因 杰克实验室，麻省理工学院和周边地区的研究环境提供无与伦比的研究环境 科学讨论，协作和培训的机会。目前，我监督本科生 学生和技术助理直接与我合作进行与我的研究有关的实验。这是 令人难以置信的体验，它将赋予我许多必要的技能来管理独立 实验室。麻省理工学院的科学界，布罗德研究所和哈佛医学院提供无数 将继续促进我的科学发展的准半货币和讲习班。 我的直接目标是开发本应用程序中描述的研究平台 展示了其发现miR-34a和其他肿瘤的分子和细胞机制的潜力 抑制miRNA。我打算启动一个独立的研究计划，以利用这些计划 通过在多种肿瘤模型中研究肿瘤抑制剂miRNA通过研究体内系统。从长远来看，我是 确信这些实验将为我的研究计划提供坚实的基础 之上。我期待着教育和招募分享我对癌症热情的学生和博士后 研究。