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

项目摘要/摘要 我的研究重点是阐明microrna在其中发挥作用的细胞和分子机制。 癌症。MicroRNA(MiRNA)分子已经成为许多生物过程的重要调节器， 包括癌症。已知许多抑癌基因miRNAs在肿瘤中低表达。然而， 这些miRNAs抑制肿瘤进展的能力以及miRNAs是否可以用于治疗 用来治疗癌症的药物在体内模型中还没有得到很好的证实。在此K99/R00范围内提出的项目 该奖项概述了新型条件miRNA表达系统纳米粒子的创建和实施 传递系统，以及允许研究小鼠和人的microRNA的miRNA靶标识别管道 癌症模型。 在这项申请中提出的研究是根据我研究p53肿瘤的经验而形成的- 抑制基因修复，确定肝癌中的肿瘤抑制基因，进行体内shRNA筛选， 并通过我最近的努力来阐明核因子-kB抑制剂在肺癌中的治疗效果。这些研究 项目巩固了我从事肿瘤抑制基因基础生物学研究的兴趣 MiRNA在人类癌症进展和治疗中的作用，因为miR-34等miRNA是新出现的 重要的肿瘤抑制途径。我们在这里提出的系统利用本地小鼠 模型和基因定义的人类癌细胞。这项研究将把遗传学、生物信息学和 翻译纳米技术研究miR-34‘S在肺癌发生发展中的作用及评价miR-34 家庭作为一种潜在的肺癌治疗剂。麻省理工学院科赫研究所的设施，以及 我的导师杰克斯博士可以提供的专业知识对成功实施这一点将是无价的 项目。 文中概述的这些实验的目标是： ·阐明miR-34a抑制肺癌进展的机制 ·发展纳米技术，在小鼠和人肺癌中系统地输送miR-34a 模型 ·识别和验证与人类肺癌相关的新miR-34a靶基因 麻省理工学院贾克斯实验室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，我指导一名本科生 一名学生和一名技术助理，他们直接与我一起进行与我研究相关的实验。这是 一次令人难以置信的经历，将赋予我许多必要的技能来管理独立的 实验室。麻省理工学院、博德研究所和哈佛医学院的科学界提供了无数 研讨会和研讨会将继续促进我的科学发展。 我的近期目标是开发此应用程序中描述的研究平台，并 证明其有可能揭示miR-34a和其他肿瘤的分子和细胞机制 抑制因子miRNAs。我打算启动一个独立的研究计划，以利用这些 通过研究各种肿瘤模型中的肿瘤抑制因子miRNAs，研究体内系统。从长远来看，我是 我相信这些实验将为我的研究计划奠定坚实的基础 在那里。我期待着教育和招收和我一样热爱癌症的学生和博士后 研究。

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.