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

描述（申请人提供）：我的研究重点是阐明microRNAs在癌症中的细胞和分子机制。microRNA （miRNA）分子已成为包括癌症在内的许多生物过程的重要调节因子。众所周知，许多肿瘤抑制mirna在癌症中低表达。然而，这些miRNAs抑制肿瘤进展的能力以及miRNAs是否可以用于治疗癌症还没有在体内模型中得到很好的证实。K99/R00奖项中提出的项目概述了新的条件miRNA表达系统，纳米颗粒传递系统和miRNA靶标识别管道的创建和实施，这些管道允许在小鼠和人类癌症模型中研究microRNA。本申请中提出的研究是由我研究p53肿瘤抑制基因恢复、识别肝癌中的肿瘤抑制基因、进行体内shRNA筛选的经验以及我最近阐明NF-kB抑制剂在肺癌中的治疗作用的努力形成的。这些研究项目巩固了我从事肿瘤抑制miRNA在人类癌症进展和治疗中的基础生物学研究的兴趣，因为像miR-34这样的miRNA是重要肿瘤抑制途径的新兴介质。我们在此提出的系统利用原生小鼠模型和基因定义的人类癌细胞。本研究将结合遗传学、生物信息学和转化纳米技术，研究miR-34在肺癌发生发展中的功能，并评估miR-34家族作为潜在的肺癌治疗剂。麻省理工学院科赫研究所的设施和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个项目是非常宝贵的。这些实验概述的目标是：阐明miR-34a抑制肺肿瘤进展的机制；开发纳米技术系统地在小鼠和人肺肿瘤模型中传递miR-34a；识别和验证与人类肺癌相关的新型miR-34a靶基因。麻省理工学院Jacks实验室及其周边地区的研究环境为科学讨论、合作和培训提供了无与伦比的机会。目前，我指导一名本科生和一名技术助理，他们直接与我一起进行与我的研究有关的实验。这是一个不可思议的经历，它将赋予我许多必要的技能来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的研讨会和讲习班，这些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，并展示其揭示miR-34a和其他肿瘤抑制mirna的分子和细胞机制的潜力。我打算启动一个独立的研究项目，通过研究各种肿瘤模型中的肿瘤抑制mirna来利用这些体内系统。从长远来看，我相信这些实验将为我的研究项目奠定坚实的基础。我期待着教育和招募和我一样热爱癌症研究的学生和博士后。

DESCRIPTION (provided by applicant): 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 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.