CHARACTERIZATION OF SEXUAL DIMORPHISM IN GLIOMA METABOLISM

项目摘要 NIH K99/R00独立之路奖的目标是让自己成为一名独立人士 脑胶质瘤代谢成像领域的研究人员。我的研究计划利用了我现有的知识 肿瘤新陈代谢与胶质瘤研究的新培训和新经验，特别是与性别有关的研究 脑胶质瘤发生机制的差异。具体地说，我将定义性和性之间的互动 胶质瘤驱动基因突变作为糖代谢调节因子对胶质瘤表型的影响及确定 葡萄糖代谢的性别差异的发育起源是什么？ 在康奈尔大学获得本科学位后，我考上了医学院 华盛顿大学的科学家培训计划。我的论文集中在前列腺神经内分泌(NE)。 癌症新陈代谢，整合表达谱和分析化学技术以识别丰富的 高级别东北地区癌症的代谢特点。当我回到医学培训时，我的临床兴趣集中在 在放射学诊断方面。作为一名未来的内科科学家，我觉得肿瘤学成像的研究生涯将 代表了我的研究和临床兴趣的理想结合。 我对影像研究的兴趣使我留在了华盛顿的Mallinckrodt放射研究所 在华盛顿大学的临床诊断放射学住院医师项目中接受培训。 实习结束后，我接受了为期一年的临床体磁共振研究，重点是肿瘤学成像。 在这次培训中，我对分子成像和癌症新陈代谢的结合产生了兴趣，以确定 对癌症患者进行分层的新方法，并为他们开发新的治疗方案。 到目前为止，我的临床培训使我对解剖成像技术有了广泛的了解。论 另一方面，我的研究培训帮助建立了一个框架，以了解癌症新陈代谢和 用来研究它的技术。我职业生涯下一阶段的目标是在这两者之间架起一座桥梁 发展脑瘤生物学和小动物成像方面的专业知识，以了解机制 脑肿瘤发生和代谢中潜在的性别差异。 我已经制定了一项培训计划，精选放射科和西特曼的优势 华盛顿大学癌症中心提供必要的专业知识和先进的基础设施 技术。对于我获奖的K99部分，我将住在我的导师约书亚博士的实验室里 鲁宾是癌症性别差异领域的专家。在那里，我将获得理论和实践方面的经验 研究脑瘤生物学所需的技术。除此之外，还将有课程作业、研讨会和 会议，以加强我的培训，将为未来的职业生涯提供坚实的基础，包括癌症 新陈代谢和成像。我还将通过以下方式进行翻译研究设计的教学培训 华盛顿大学临床与翻译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。我会过渡到一个独立的实验室 在R00阶段，我将汇集新方法和对肿瘤新陈代谢的生物学见解。 这项研究建议建立在肿瘤学领域的一个新兴范式之上。在许多癌症中 在人体内，男性不仅比女性有更高的恶性肿瘤发生率，而且他们还 病情越差，复发时间越短，总体生存时间越短。这一点对于 多形性胶质母细胞瘤(GBM)是一种预后极差的侵袭性胶质瘤。尽管 这一现象背后的机制仍有待阐明，我认为 葡萄糖代谢可能开始解释这些观察到的现象。在鲁宾博士的指导下，我将 开发新的动物模型以确定与GBM性别差异有关的机制。 我的长期目标是了解为什么男性癌症患者比女性患者表现更差的代谢基础 癌症患者。这一提议将检验中心假设，即葡萄糖代谢中的性别差异 性别差异在基底膜肿瘤发生中的作用。在第一个目标中，我们将研究糖酵解的作用- 利用技术促进癌症突变PTEN和EGFR在性别特异性肿瘤发生和代谢中的作用 由鲁宾博士的实验室开发，结合稳定同位素标记、新陈代谢研究和PET成像。 在第二个目标中，我们将确定葡萄糖代谢性别差异的发育起源。我们会 利用癌症生物学领域的新发现的两种动物模型来鉴定性染色体的作用 宫内暴露性激素对星形胶质细胞葡萄糖代谢的补充和表观遗传效应。 这项研究提案是创新的，因为它将开始识别癌症中不同性别的差异 新陈代谢，一个未被触及的领域。这项提案中概述的实验将产生对 糖代谢性别差异背后的机制及致癌关键驱动因素的影响 表型。我预计这将为新的可翻译的成像方法提供一个平台，并 不仅是脑瘤的治疗方法，而且是一般癌症的治疗方法。

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.