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）分子已经成为许多生物过程（包括癌症）的重要调节剂。众所周知，许多肿瘤抑制器中的miRNA在癌症中表现较低。但是，这些miRNA限制肿瘤进展的能力以及在体内模型中是否可以治疗miRNA是否可以治疗治疗癌症。该项目在本K99/R00奖中提出的项目概述了新型有条件miRNA表达系统，纳米粒子递送系统和miRNA靶标识别管道的创建和实施，这些识别管道允许研究小鼠和人类癌症模型中的microRNA。 我在研究p53肿瘤抑制基因恢复，鉴定肝癌中抑制肿瘤抑制因子，在体内SHRNA筛查中以及我最近阐明NF-KB抑制剂在肺癌中的治疗作用的努力的经验所塑造了该应用中提出的研究。这些研究项目巩固了我在追求人类癌症进展和治疗中研究肿瘤抑制miRNA的基本生物学的职业生物学方面的兴趣，因为miR-34（例如miR-34）是重要肿瘤抑制途径的新兴介体。我们在本文提出的系统利用自动围绕小鼠模型和遗传定义的人类癌细胞。这项研究将整合遗传学，生物信息学和转化纳米技术，以研究miR-34在肺癌开发中的功能，并评估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以及我的导师杰克斯博士提供的专业知识对于成功实施该项目是无价的。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模型中的miR-34a； 识别和验证与人肺癌相关的新型miR-34a靶基因研​​究环境，麻省理工学院和周边地区的研究环境为科学讨论，协作和培训提供了无与伦比的机会。目前，我监督了一名本科生和一名技术助理，该技术助理直接与我合作进行与我的研究有关的实验。这是一次令人难以置信的体验，它将赋予我许多管理独立实验室的必要技能。麻省理工学院，布罗德研究所和哈佛医学院的科学界提供无数的研讨会和讲习班，这些研讨会将继续促进我的科学发展。 我的近期目标是开发本应用中描述的研究平台，并证明其可能发现miR-34a和其他肿瘤抑制器miRNA的分子和细胞机制的潜力。我打算启动一个独立的研究计划，该计划将通过在各种肿瘤模型中研究肿瘤抑制剂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提供坚实的基础。我期待教育和招募与我对癌症研究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剂。该项目着重于p53受监管的miRNA miR-34家族。我的目标是开发小鼠和人类模型，以研究miR-34在肺部肿瘤发育和治疗中的功能。我将探讨miR-34抑制肺肿瘤进展，发展纳米技术以治疗治疗的机制，并鉴定小鼠和人肺癌细胞中新型的miR-34靶基因。