The molecular mechanism of isocitrate dehydrogenase (lDH) mutations in cancer

异柠檬酸脱氢酶（IDH）突变在癌症中的分子机制

基本信息

批准号：
8752659
负责人：
Christal Dyane Sohl
金额：
$ 9万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-07 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8752659
关键词：
Acute Myelocytic Leukemia Address Adult Advisory Committees Affinity Antioxidants Binding Biological Assay Catalysis Categories Cells Cellular Assay Characteristics Chemistry Data Analyses Decarboxylation Defect Development Dimerization Dissociation Educational workshop Enzymes Foundations Functional disorder Future Glioblastoma Glioma Glutathione Goals Gold Grant Health Human Isocitrate Dehydrogenase Isocitrates Isoprostanes Kinetics Laboratories Link Malignant Neoplasms Manuscripts Mass Spectrum Analysis Measures Mediating Mentors Mentorship Metabolic Microspectrophotometry Molecular Mutate Mutation NADP Natural regeneration Oncogene Proteins Oncogenic Oxidative Stress Pathway interactions Patients Physiologic pulse Play Point Mutation Positioning Attribute Preparation Production Qualifying Reaction Relative (related person)Reporting Research Role Structure Students Techniques Testing Therapeutic Time Training Tumor Suppression Tumor Suppressor Genes Universities Work Writing X-Ray Crystallography biophysical techniques career career development design enzyme mechanism gain of function improved isocitrate millisecond mutant new technology novel overexpression oxidation oxidative damage prevent programs stem symposium therapy design tool tumor tumor metabolism tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Although metabolic alterations in tumors were first described nearly a century ago, it has only been within the last decade that changes in the activity of metabolic enzymes have been directly linked to tumorigenesis. Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), the enzymes responsible for the NADP+- dependent conversion of isocitrate (ICT) to ?-ketoglutarate (¿KG), are mutated in over 80% of adult grade II and grade III gliomas and secondary glioblastomas, and up to 20% of acute myeloid leukemias. Intriguingly, many IDH mutations may serve as both tumor suppressors and oncogenes; all mutations characterized to date result in significant deficiency in ICT turnover, but surprisingly, many also gain a novel neomorphic activity. Instead of the normal oxidative decarboxylation, many IDH mutants catalyze the NADPH-dependent reduction of ¿KG to the proposed oncometabolite, 2-hydroxyglutarate (2HG). This proposal seeks to elucidate the catalytic pathway and structural features of tumorigenic IDH mutations to elucidate the molecular mechanisms of dysfunction that support oncogenesis using pre-steady-state kinetics, biophysical methods, X-ray crystallography, microspectrophotometry, and cellular assays. This will clarify the contributions of deficient normal activity and neomorphic activity in enzymatic dysfunction, and how structural alterations influence these contributions. Further, the potential for IDH mutations to cause oxidative stress will be explored to identify important tumorigenic pathways. Such studies provide a critical foundation to aid the design of effective IDH-targeted therapy, and to help predict which mutations in patients will likely be amenable to such treatment. The long-term career goal is to establish an independent academic research program examining the molecular mechanisms of enzymatic dysfunction in metabolic enzymes, and how these mechanisms contribute to oncogenesis. To achieve this, two major short-term goals include gaining the significant training required to complete the aims of the project, and receiving career development mentoring. An advisory committee of experts of many of the techniques proposed has been assembled to assist in experimental training and data analysis and to provide mentorship in career development. This will supplement the vital mentoring and training provided by the postdoctoral mentor. Further support will come from collaborators, who are experts in the remaining techniques described in this proposal. Attendance at career development workshops and seminars at Yale University, and at courses at Yale University, the Brookhaven National Laboratory, and Cold Spring Harbor will provide required training and development. Finally, opportunities for manuscript preparation, grant writing, mentoring students, giving talks, and presenting at conferences will further support the long term goal of leading a successful independent research program. By gaining experimental training and seeking out opportunities for career development, I will acquire the tools necessary to develop an independent research program exploring the molecular mechanisms of defects in cancer metabolism.

描述（由适用提供）：尽管大约一个世纪前首次描述了肿瘤的代谢改变，但仅在过去的十年之内，代谢酶活性的变化已与肿瘤发生直接相关。异位酸盐脱氢酶1和2（IDH1和IDH2），负责NADP+ - 依赖性 - 依赖性的异位酸酯（ICT）转化为？-ketogoglutarate（�KG），在超过80％的成人III级gliomas和III级gliomas和Sependary Glioblastomas和Septimarlastomas和sependary Glioblastomas和Up and areel中的80％以上是超过80％。有趣的是，许多IDH突变既可以用作肿瘤补充剂又可以充当癌基因。迄今为止，所有突变都会导致ICT周转率严重缺乏，但令人惊讶的是，许多突变也获得了新型的新形态活性。许多IDH突变体不是正常的氧化脱羧，而是催化了NADPH依赖性的«kg降低至拟议的oncometabolite，2-羟基戊二酸（2HG）。该提案旨在阐明肿瘤性IDH突变的催化途径和结构特征，以阐明使用前稳态动力学，生物物理学，X射线晶体学，微光谱仪和细胞分析的功能障碍的分子机制，这些功能障碍的分子机制。这将阐明酶功能障碍中缺乏正常活动和新形态活性的贡献，以及结构改变如何影响这些贡献。此外，将探索IDH突变引起氧化应激的潜力，以鉴定重要的肿瘤途径。这样的研究为有效的IDH靶向疗法设计提供了关键的基础，并有助于预测患者的哪些突变可能可以接受这种治疗。长期职业目标是建立一个独立的学术研究计划，研究代谢酶中酶促功能障碍的分子机制，以及这些机制如何促进肿瘤发生。为了实现这一目标，两个主要的短期目标包括获得完成该项目目标所需的重大培训，并获得职业发展指导。拟议的许多技术的专家咨询委员会已经组装，以协助实验培训和数据分析并提供职业发展的心态。这将补充博士后心态提供的重要心理和培训。进一步的支持将来自合作者，他们是本提案中剩余技术的专家。参加耶鲁大学的职业发展研讨会和下水道，在耶鲁大学，布鲁克黑文国家实验室和冷泉港的课程将提供所需的培训和发展。最后，手稿准备，赠款写作，心理学生，发表演讲以及在会议上的介绍的机会将进一步支持领导成功的独立研究计划的长期目标。通过获得实验性培训并寻求职业发展的机会，我将获得开发独立研究计划所需的工具，以探索癌症代谢中缺陷的分子机制。