Establishing therapeutic efficacy and uncovering mechanisms of tumor suppression

确定治疗功效并揭示肿瘤抑制机制

• 批准号: 8616117
• 负责人: David Feldser
• 金额: $ 23.41万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616117
• 关键词: Alleles; Area; Attention; Award; Biochemical; Biochemical Pathway; Biological; Biological Assay; Biology; Burkitt Lymphoma; Cancer Biology; Cancer Model; Cancer cell line; Cell Culture Techniques; Cell Line; Cell model; Cells; Collaborations; Communities; Data; Development; Educational workshop; Embryo; Environment; Epithelial Cells; Fibroblasts; Fostering; Foundations; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Silencing; Genes; Genetic; Glean; Goals; Human; In Vitro; Institutes; Intention; Laboratories; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mentors; Modeling; Molecular; Mouse Cell Line; Mus; Mutate; Organism; Pathway interactions; Phenotype; Postdoctoral Fellow; Prostate; Prostatic Neoplasms; Protein p53; Recruitment Activity; Research; Research Project Grants; Shapes; Site; Students; System; Systems Analysis; Therapeutic; Therapeutic Intervention; Tissues; Training; Treatment Efficacy; Tumor Biology; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor-Suppressor Gene Inactivation; Work; abstracting; anticancer research; cancer cell; career; cellular engineering; comparative; experience; gene function; in vivo; interest; medical schools; mouse model; neoplastic cell; new therapeutic target; novel; programs; recombinase; research study; restoration; skills; telomere; tool; tumor; tumor progression; undergraduate student

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.

项目概要/摘要 我的研究重点是阐明细胞和分子机制 众所周知，细胞具有内在和外在的肿瘤。 由一些关键的肿瘤抑制基因精心策划的抑制机制。 然而，在已形成的肿瘤中无法随意恢复抑癌功能 妨碍了我们对 K99/R00 奖项中提出的项目的理解。 概述了允许基因失活的新型小鼠模型的创建和实施 并以组织特异性和时间方式控制基因恢复。 本申请中提出的研究是由我的经验决定的 研究伯基特淋巴瘤模型中端粒功能障碍的后果以及我的研究 最近努力阐明恢复 p53 肿瘤抑制基因的体内作用 这些研究项目巩固了我对不同人类癌症的兴趣。 从事研究人类癌症进展的基本组成部分的职业。 探究肿瘤抑制生物学的愿望需要开发遗传小说 肿瘤抑制基因功能可以被灭活的系统，然后随后 我们建议的系统利用本地小鼠模型并进行恢复。 对这些系统进行基因定义的比较分析将增强。 通过利用相关的发现肿瘤抑制的基本机制 研究人类癌症的体内环境和相关生物体。 麻省理工学院的科赫研究所，以及我的导师杰克斯博士可以提供的专业知识将是 对于该项目的成功实施具有不可估量的价值。 其中概述的这些实验的目标是： ¿强调针对这些肿瘤抑制剂的治疗潜力 途径作为根除癌症的手段， ¿确定肿瘤抑制基因抑制的相关机制 多种肿瘤类型的癌症形成或进展， ¿揭示肿瘤抑制基因释放的生物程序 恢复，以及 ¿确定治疗干预的具体新目标。 麻省理工学院杰克斯实验室及周边地区的研究环境提供了 目前，我拥有无与伦比的科学讨论、合作和培训机会。 监督一名本科生和一名直接与我一起工作的技术助理 与我的研究相关的实验是一次令人难以置信的经历，它将赋予我很多东西。 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举办了无数研讨会和讲习班 这将继续促进我的科学发展。 我的近期目标是开发此应用程序中描述的研究平台 并证明其解锁迄今为止未表征的分子和细胞的潜力 我打算启动一个独立的研究计划。 将通过研究多个肿瘤抑制基因来利用这些体内系统 从长远来看，我相信这些实验将会对各种重要的肿瘤类型产生影响。 为我的研究项目的发展奠定基础，我期待着教育和发展。 招募与我一样对癌症研究充满热情的学生和博士后。