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: 8353069
• 负责人: Wen Xue
• 金额: $ 11.04万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8353069
• 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 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; 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

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. PUBLIC HEALTH RELEVANCE: microRNAs are important regulators of biological pathways. This project focuses on a p53 regulated miRNA miR-34 family. My goals are to develop mouse and human models to investigate the function of miR-34 in lung tumor development and therapy. I will explore the mechanisms by which miR-34 inhibits lung tumor progression, develop nano-technology to therapeutically deliver miR-34, and identify novel miR-34 target genes in mouse and human lung cancer cells.

描述（由申请人提供）：我的研究重点是阐明 microRNA 在癌症中发挥的细胞和分子机制。 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 miRNA 抑制肿瘤进展的能力以及 miRNA 是否可以通过治疗方式递送来治疗癌症尚未在体内模型中得到很好的建立。 K99/R00 奖项中提出的项目概述了新型条件 miRNA 表达系统、纳米颗粒递送系统和 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基于我研究 p53 肿瘤抑制基因恢复、鉴定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 抑制剂在肺中的治疗效果的努力癌症。这些研究项目巩固了我对人类癌症进展和治疗中肿瘤抑制 miRNA 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本土小鼠模型和基因定义的人类癌细胞。本研究将整合遗传学、生物信息学和转化纳米技术来研究miR-34在肺癌发生发展中的功能，并评估miR-34家族作为肺癌潜在治疗剂的作用。麻省理工学院科赫研究所的设施以及我的导师 Jacks 博士所能提供的专业知识对于成功实施该项目将非常宝贵。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，在小鼠和人类肺肿瘤模型中系统地递送 miR-34a； 识别并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相关的实验。这是一次令人难以置信的经历，它将赋予我管理独立实验室的许多必要技能。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，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-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计划奠定坚实的基础。我期待着教育和招募与我一样对癌症研究充满热情的学生和博士后。 公共卫生相关性： microRNA 是生物途径的重要调节因子。该项目重点关注 p53 调节的 miRNA miR-34 家族。我的目标是开发小鼠和人类模型来研究 miR-34 在肺肿瘤发展和治疗中的功能。我将探索 miR-34 抑制肺癌进展的机制，开发纳米技术来治疗性递送 miR-34，并在小鼠和人类肺癌细胞中鉴定新的 miR-34 靶基因。