Establishing therapeutic efficacy and uncovering mechanisms of tumor suppression

项目摘要/摘要 我的研究重点是阐明细胞和分子机制 抑制恶性肿瘤。众所周知，细胞具有内在和外在的肿瘤- 由几个关键的肿瘤抑制基因协调的抑制机制。 然而，在已建立的肿瘤中，无法随意恢复肿瘤抑制功能 阻碍了我们对其功能的理解。本K99/R00奖项中建议的项目 概述了允许基因失活的新型小鼠模型的创建和实施 以及以特定于组织和时间的方式控制的基因恢复。 这项申请中提出的研究是由我的经验决定的 在Burkitt淋巴瘤模型中研究端粒功能障碍的后果 近年来为阐明恢复p53抑癌基因的体内效应所做的努力 几种不同的人类癌症模型。这些研究项目巩固了我对 从事研究人类癌症进展的基本组成部分的职业。我的 对肿瘤抑制生物学的渴望要求开发新的基因 肿瘤抑制基因功能可以失活并随后 恢复了。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。对这些系统的比较分析将加强 利用相关基因发现肿瘤抑制的基本机制 活体环境和研究人类癌症的相关组织。该中心的设施 麻省理工学院的科赫研究所和我的导师贾克斯博士所能提供的专业知识将是 对于这一项目的成功实施来说，这是无价的。 文中概述的这些实验的目标是： ？强调靶向这些肿瘤抑制因子的治疗潜力 作为根除癌症的一种手段， ？确定肿瘤抑制基因抑制的相关机制 癌症在各种类型的肿瘤中形成或发展， 揭开针对抑癌基因的生物程序 修复，以及 ？确定用于治疗干预的特定新靶点。 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、协作和培训机会。目前，我 指导一名本科生和一名技术助理，他们直接与我合作 与我的研究有关的实验。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。科学界在 麻省理工学院、博德研究所和哈佛医学院提供了无数的研讨会和工作坊 这将继续促进我的科学发展。 我的近期目标是开发这个应用程序中描述的研究平台 并展示了它解开迄今尚未确定的分子和细胞的潜力 肿瘤抑制的机制。我打算开始一个独立的研究项目 它将通过研究体内的多个肿瘤抑制基因来利用这些体内系统 各种重要的肿瘤类型。从长远来看，我相信这些实验将 为我的研究项目的发展提供了一个基础。我期待着教育和 招收和我一样热爱癌症研究的学生和博士后。

Project Summary/Abstract My research is focused on elucidating the cellular and molecular mechanisms that constrain malignant cancers. It is known that cells possess intrinsic and extrinsic tumor- suppressor mechanisms that are orchestrated by a handful of key tumor-suppressor genes. However, the inability to restore tumor suppressor function at will in established tumors has hampered our understanding of their functions. The project proposed within this K99/R00 award outlines the creation and implementation of novel mouse models that allow gene inactivation and gene restoration to be controlled in a tissue-specific and temporal manner. The research proposed within this application has been shaped by my experiences studying the consequences of telomere dysfunction in a model of Burkitt's lymphoma and by my recent efforts to elucidate the in vivo effects of restoring the p53 tumor-suppressor gene in several models of diverse human cancers. These research projects solidified my interests in pursuing a career studying the fundamental components of human cancer progression. My desire to interrogate the biology of tumor-suppression requires the development of novel genetic systems in which tumor-suppressor gene function can be inactivated and then subsequently restored. The systems that we propose herein utilize autochthonous mouse models and genetically defined human cancer cells. Comparative analysis of these systems will enhance discovery of fundamental mechanisms of tumor suppression by capitalizing on the relevant in vivo setting and the relevant organism in which to study human 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: ¿ to highlight the therapeutic potential of targeting these tumor-suppressor pathways as a means to eradicate cancer, ¿ to identify relevant mechanisms by which tumor-suppressor genes inhibit cancer formation or progression in a variety of tumor types, ¿ to uncover biological programs unleashed upon tumor-suppressor gene restoration, and ¿ to identify specific novel targets for therapeutic intervention. 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 unlock heretofore uncharacterized molecular and cellular mechanisms of tumor suppression. It is my intention to start an independent research program that will capitalize on these in vivo systems by studying multiple tumor-suppressor genes in a variety of important tumor types. For the long-term, I am confident that these experiments will provide a foundation on which my research program can grow. I look forward to educating and recruiting students and postdocs that share my passion for cancer research.