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

描述（由申请人提供）：我的研究重点是阐明microRNA在癌症中发挥作用的细胞和分子机制。microRNA（miRNA）分子已经成为许多生物过程（包括癌症）的重要调节剂。已知许多肿瘤抑制miRNA在癌症中低表达。然而，这些miRNA抑制肿瘤进展的能力以及miRNA是否可以治疗性地递送以治疗癌症还没有在体内模型中很好地建立。K99/R 00奖项中提出的项目概述了新型条件性miRNA表达系统、纳米颗粒递送系统和miRNA靶向识别管道的创建和实施，这些系统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、鉴定肝癌中的肿瘤抑制因子、进行体内shRNA筛选的经验以及我最近阐明NF-κ B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的兴趣，在追求职业生涯中研究肿瘤抑制miRNA在人类癌症进展和治疗中的基础生物学，因为像miR-34这样的miRNA是重要肿瘤抑制途径的新兴介质。我们在本文中提出的系统利用本地小鼠模型和遗传定义的人类癌细胞。本研究将结合遗传学、生物信息学和纳米翻译技术，研究miR-34在肺癌发生发展中的作用，并评估miR-34家族作为肺癌治疗药物的潜力。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所能提供的专业知识，对于成功实施这个项目将是无价的。本文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;开发纳米技术以在小鼠和人肺肿瘤模型中系统地递送miR-34 a;识别和验证与人类肺癌相关的新miR-34 a靶基因麻省理工学院Jacks实验室的研究环境，周边地区为科学讨论、合作和培训提供了无与伦比的机会。目前，我监督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。这是一个令人难以置信的经验，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，并证明其揭示miR-34 a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，通过在各种肿瘤模型中研究肿瘤抑制miRNAs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计划奠定坚实的基础。我期待着教育和招募学生和博士后分享我对癌症研究的热情。

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.