CHARACTERIZATION OF SEXUAL DIMORPHISM IN GLIOMA METABOLISM

神经胶质瘤代谢中性二态性的特征

基本信息

批准号：
9371209
负责人：
Joseph Edward Ippolito
金额：
$ 15.13万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9371209
关键词：
Address Adult Age Analytical Chemistry Animal Model Area Astrocytes Award Bachelor&apos s Degree Basic Science Biochemical Biological Biological Assay Brain Brain Neoplasms Cancer Biology Cancer Center Cancer Patient Carbon Characteristics Chromosomes Clinical Clinical Sciences Data Development Diagnostic radiologic examination Disease Dominant-Negative Mutation Dose EGFR gene Embryo Employee Strikes Epidermal Growth Factor Receptor Epigenetic Process Etiology Exercise Exhibits Exposure to Fellowship Female Fertilization Foundations Future Gene Expression Profiling Genes Genetic Genotype Glioblastoma Glioma Glucose Glycolysis Goals Gonadal Steroid Hormones Growth Harvest Human body Image Imaging Techniques In Vitro Incidence Institutes Instruction Knowledge Label Laboratories Life Magnetic Resonance Imaging Malignant Neoplasms Medical Mentors Mesenchymal Metabolic Metabolic Pathway Metabolism Methods Modeling Modification Molecular Profiling Mus Mutation Neurosecretory Systems Ovary PTEN gene Pathway interactions Pentosephosphate Pathway Phase Phenotype Physicians Ploidies Positron Positron-Emission Tomography Preparation Prostate Radiology Specialty Relapse Research Research Infrastructure Research Personnel Research Proposals Research Training Residencies Resistance Rest Role Scientist Sex Characteristics Sex Chromosomes Solid Stable Isotope Labeling TP53 gene Techniques Technology Testing Testis Therapeutic Time Training Training Programs Translating Translational Research Tumor Biology United States National Institutes of Health Universities Washington Woman actionable mutation anatomic imaging animal imaging c-erbB-1 Proto-Oncogenes cancer cell cancer diagnosis cancer imaging career clinical diagnostics conventional therapy design epidermal growth factor receptor VIII experience experimental study fluorodeoxyglucose fluorodeoxyglucose positron emission tomography glucose metabolism glucose uptake imaging modality in utero in vitro Assay in vivo innovation insight interest male malignant phenotype meetings men metabolic abnormality assessment metabolic imaging molecular imaging molecular subtypes mouse model mutant novel oncology outcome forecast overexpression oxidation patient stratification postnatal prenatal exposure programs pup relating to nervous system sex sexual dimorphism stable isotope theories transcriptome sequencing tumor tumor metabolism tumorigenesis

项目摘要

Project Summary The goal of this NIH K99/R00 Pathway to Independence Award is to establish myself as an independent investigator in the field of metabolic imaging of gliomas. My research plan leverages my existing knowledge of cancer metabolism with new training and experience in glioma research, specifically as it pertains to sex differences in glioma tumorigenesis. Specifically, I will define how interactions between sex and common glioma driver mutations as regulators of glucose metabolism impact on glioma phenotype and to determine what the developmental origins are for sex differences in glucose metabolism. After having received my undergraduate degree from Cornell University, I matriculated to the Medical Scientist Training Program at Washington University. My thesis focused on prostate neuroendocrine (NE) cancer metabolism, integrating expression profiling and analytical chemistry techniques to identify enriched metabolic features of high grade NE cancers. When I returned to medical training, my clinical interests focused on diagnostic radiology. As a future physician-scientist, I felt that a research career in oncologic imaging would represent an ideal combination of my research and clinical interests. My interest in imaging research led me to stay at the Mallinckrodt Institute of Radiology at Washington University in St. Louis for training in a clinical diagnostic radiology residency program at Washington University. Following residency, I trained in a one year clinical Body MRI fellowship with a focus on oncologic imaging. During this training, I developed an interest in merging molecular imaging and cancer metabolism to identify new ways to stratify cancer patients and develop new treatment options for them. To date, my clinical training has provided a broad understanding of anatomic imaging techniques. On the other hand, my research training has helped establish a framework to understand cancer metabolism and the techniques used to study it. The goal of the next phase of my career is to develop a bridge between these two areas, developing expertise in brain tumor biology and small animal imaging to understand mechanisms underlying sex differences in brain tumorigenesis and metabolism. I have developed a training plan that culls the strengths of the Department of Radiology and the Siteman Cancer Center at Washington University to supply the necessary infrastructure of expertise and advanced technologies. For the K99 portion of my award, I will be housed in the laboratory of my mentor, Dr. Joshua Rubin, an expert in the field of sex differences in cancer. There, I will gain experience in the theory and techniques required to study brain tumor biology. This will be supplemented with coursework, seminars, and meetings to enhance my training that will provide a solid foundation for a future career that integrates cancer metabolism and imaging. I will also engage in didactic training in the design of translational research through the Institute of Clinical and Translational Sciences through Washington University in preparation for future projects that translate my basic science discoveries to the clinical setting. I will transition to an independent lab in the R00 phase where I will bring together novel methods and biological insights into tumor metabolism. This research proposal builds upon an emerging paradigm in the field of oncology. In many cancers throughout the human body, males not only have a higher incidence of malignancy than females, but they also do worse characterized by shorter relapse times and shorter overall survival. This is particularly true for glioblastoma multiforme (GBM), an extraordinarily aggressive glioma with dismal prognosis. Although the mechanisms underlying this phenomenon remain to be elucidated, I propose that inherent sex differences in glucose metabolism may begin to explain these observed phenomena. Under the instruction of Dr. Rubin, I will develop new animal models to identify mechanisms involved in sex differences in GBM. My long term goal is to understand the metabolic basis of why male cancer patients do worse than female cancer patients. This proposal will test the central hypothesis that sex differences in glucose metabolism underlie sex differences in GBM tumorigenesis. In the first aim, we will investigate the role of glycolysis- enhancing cancer mutations PTEN and EGFR in sex-specific tumorigenesis and metabolism using techniques developed in Dr. Rubin’s lab in combination with stable isotope labeling metabolism studies and PET imaging. In the second aim, we will identify the developmental origins of sex differences in glucose metabolism. We will use two animal models, novel to the cancer biology field, to identify the effects of sex chromosome complement and epigenetic effects of in utero exposure to sex hormones on astrocyte glucose metabolism. This research proposal is innovative because it will begin to identify sex-specific differences in cancer metabolism, an untouched field. The experiments outlined in this proposal will generate new insights into the mechanism behind sex differences in glucose metabolism and the impact of key drivers of the malignant phenotype. I anticipate that this will provide a platform for novel readily-translatable imaging methods and therapeutic approaches to not only brain tumors, but cancer in general.

项目摘要这项NIH K99/R00独立奖的目标是将自己确立为独立神经胶质瘤代谢成像领域的研究者。我的研究计划利用了我现有的知识癌症代谢具有新的胶质瘤研究培训和经验，特别是与性有关神经胶质瘤肿瘤发生的差异。具体来说，我将定义性别与共同点之间的互动神经胶质瘤驱动突变是葡萄糖代谢对神经胶质瘤表型的影响并确定葡萄糖代谢性别差异的发展起源是什么。在获得康奈尔大学的本科学位后，我明白地去了医学华盛顿大学的科学家培训计划。我的论文专注于前列腺神经内分泌（NE）癌症代谢，整合表达分析和分析化学技术以鉴定富集高级NE癌的代谢特征。当我回到医学培训时，我的临床兴趣集中关于诊断放射学。作为未来的身体科学家，我觉得肿瘤学成像的研究职业将代表了我的研究和临床兴趣的理想组合。我对成像研究的兴趣使我留在华盛顿的Mallinckrodt放射学院圣路易斯大学在华盛顿大学接受临床诊断放射学宿舍计划培训。居住之后，我接受了一年的临床MRI奖学金培训，重点是肿瘤成像。在这次培训期间，我对合并分子成像和癌症代谢的兴趣识别分层癌症患者并为他们开发新的治疗选择的新方法。迄今为止，我的临床培训为解剖成像技术提供了广泛的了解。在另一方面，我的研究培训帮助建立了一个框架，以了解癌症代谢和用于研究它的技术。我职业生涯的下一阶段的目标是在这两个之间建立桥梁领域，在脑肿瘤生物学和小动物成像方面发展专业知识以了解机制脑肿瘤发生和代谢的基本性别差异。我制定了一项培训计划，以赋予放射学系和现场人的优势华盛顿大学的癌症中心，提供必要的专业知识基础设施和先进的基础设施技术。对于我奖项的K99部分，我将被安置在我的心理实验室中，约书亚博士鲁宾是癌症性别差异领域的专家。在那里，我将获得理论的经验，研究脑肿瘤生物学所需的技术。这将补充课程，半读和开会以增强我的培训，这将为将来整合癌症的职业提供坚实的基础代谢和成像。我还将通过华盛顿大学通过华盛顿大学的临床和转化科学研究所为未来做准备将我的基础科学发现转化为临床环境的项目。我将过渡到独立实验室在R00阶段，我将将新颖的方法和生物学见解融合到肿瘤代谢中。这项研究建议建立在肿瘤学领域的新兴范式上。在许多癌症中在整个人体中，男性不仅比女性更高的恶性肿瘤事件，而且他们还具有更糟糕的是，以较短的继电器时间和较短的总生存期为特征。尤其如此胶质母细胞瘤多形（GBM），这是一种非常侵略性的神经胶质瘤，预后令人沮丧。虽然我建议，这种现象的基础机制仍有待阐明葡萄糖代谢可能开始解释这些观察到的现象。在鲁宾博士的指示下，我将开发新的动物模型，以识别GBM性别差异涉及的机制。我的长期目标是了解为什么男性癌症患者比女性差的代谢基础癌症患者。该提案将检验葡萄糖代谢性别差异的中心假设 GBM肿瘤发生的性别差异基础。在第一个目标中，我们将研究糖酵解的作用 - 使用技术增强性别特异性肿瘤发生和代谢中的癌症突变和EGFR 在鲁宾博士的实验室中开发，并结合稳定的同位素标记代谢研究和宠物成像。在第二个目标中，我们将确定葡萄糖代谢中性别差异的发展起源。我们将使用两个动物模型，新的癌症生物学领域的动物模型来识别性染色体的影响子宫对性恐怖症对星形胶质细胞葡萄糖代谢的补体和表观遗传学作用。该研究建议具有创新性，因为它将开始识别癌症的性别特定差异代谢，一个未触及的领域。本提案中概述的实验将产生对该提案的新见解性别差异的机制在葡萄糖代谢和恶性驱动因素的影响表型。我预计这将为新颖易于转换的成像方法提供一个平台，并治疗方法不仅是脑肿瘤，而且总体上是癌症。