CHARACTERIZATION OF SEXUAL DIMORPHISM IN GLIOMA METABOLISM

项目摘要 这个NIH K99/R 00独立之路奖的目标是建立自己作为一个独立的 神经胶质瘤代谢成像领域的研究者。我的研究计划利用我现有的知识， 癌症代谢与神经胶质瘤研究的新培训和经验，特别是因为它涉及到性别 胶质瘤肿瘤发生的差异。具体地说，我将定义性和共同的 胶质瘤驱动突变作为葡萄糖代谢调节因子对胶质瘤表型的影响， 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，我被医学院录取。 华盛顿大学科学家培训项目。我的论文集中在前列腺神经内分泌（NE） 癌症代谢，整合表达谱和分析化学技术，以确定富集的 高级别NE癌症的代谢特征。当我回到医疗培训，我的临床兴趣集中在 诊断放射学的作为一个未来的医生科学家，我觉得在肿瘤成像的研究生涯将 代表了我的研究和临床兴趣的理想结合。 我对影像学研究的兴趣使我留在了华盛顿的马林克罗特放射学研究所 圣路易斯大学，在华盛顿大学的临床诊断放射学住院医师培训计划。 住院医师之后，我接受了为期一年的临床身体MRI研究金培训，重点是肿瘤成像。 在这次培训中，我对融合分子成像和癌症代谢产生了兴趣， 对癌症患者进行分层并为他们开发新的治疗方案的新方法。 到目前为止，我的临床培训提供了解剖成像技术的广泛理解。上 另一方面，我的研究培训帮助建立了一个框架来了解癌症代谢和癌症的发展。 我职业生涯下一阶段的目标是在这两者之间建立一座桥梁。 领域，发展脑肿瘤生物学和小动物成像方面的专业知识，以了解机制 脑肿瘤发生和代谢的潜在性别差异。 我已经制定了一个培训计划，挑选放射科和Siteman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.对于我的K99部分奖励，我将住在我的导师，约书亚博士的实验室 鲁宾是癌症性别差异领域的专家。在那里，我将获得理论方面的经验， 研究脑肿瘤生物学所需的技术。这将补充课程，研讨会， 参加会议以加强我的培训，这将为未来与癌症相关的职业生涯提供坚实的基础 代谢和成像。我还将通过以下方式参与翻译研究设计的教学培训： 临床和转化科学研究所通过华盛顿大学为未来做准备 将我的基础科学发现转化为临床的项目。我将过渡到一个独立的实验室 在R 00阶段，我将把新的方法和生物学的见解结合在一起，研究肿瘤代谢。 这项研究计划建立在肿瘤学领域的新兴范式之上。在许多癌症中 在整个人体中，男性不仅恶性肿瘤的发病率高于女性，而且 表现为复发时间更短和总生存期更短。尤其如此 多形性胶质母细胞瘤（GBM）是一种预后差的侵袭性胶质瘤。虽然 这一现象背后的机制仍有待阐明，我认为，内在的性别差异， 葡萄糖代谢可以开始解释这些观察到的现象。在鲁宾医生的指导下，我将 开发新的动物模型，以确定GBM性别差异的机制。 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。这项建议将测试的核心假设，性别差异，在葡萄糖代谢 GBM肿瘤发生的性别差异。在第一个目标中，我们将研究糖酵解的作用- 使用技术增强癌症突变PTEN和EGFR在性别特异性肿瘤发生和代谢中的作用 Rubin博士的实验室结合稳定同位素标记代谢研究和PET成像开发的。 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。我们将 使用两种癌症生物学领域新的动物模型来鉴定性染色体的影响， 子宫内暴露于性激素对星形胶质细胞葡萄糖代谢的补体和表观遗传效应。 这项研究提案是创新的，因为它将开始确定癌症的性别特异性差异 新陈代谢，一个未被触及的领域。本提案中概述的实验将对 葡萄糖代谢性别差异背后的机制以及恶性肿瘤的关键驱动因素的影响 表型。我预计，这将为新的易于翻译的成像方法提供一个平台， 不仅是脑肿瘤的治疗方法，还有一般的癌症。

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.