Project 3: Metabolic imaging of TERT expression

项目3：TERT表达的代谢成像

基本信息

批准号：
10449384
负责人：
Sabrina Miriam Ronen
金额：
$ 42.42万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449384
关键词：
6-phosphogluconate Acetoacetates Address Adenine Nucleotides Ascorbic Acid Aspartate Biological Markers Brain Neoplasms Cell Extracts Cell Line Cell Nucleus Cell Proliferation Cell physiology Cells Clinic Data Development Engineering Genetic Glioblastoma Glioma Glucose Glutathione Glutathione Disulfide Goals Image Implant Induced Mutation Lead Link Magnetic Resonance Spectroscopy Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Monitor Mutation NADP Outcome Oxidation-Reduction Oxides Patients Pentosephosphate Pathway Pharmacology Phenotype Process RNA-Directed DNA Polymerase Reaction Reactive Oxygen Species Recurrence Reporting Research Reverse Transcriptase Inhibitors Role Signal Pathway Small Interfering RNA Somatic Cell Telomerase Telomerase inhibition Testing Therapeutic Treatment Efficacy Treatment outcome base beta-Hydroxybutyrate brain parenchyma cancer cell care outcomes drug development genetically modified cells imaging approach imaging biomarker imaging modality improved improved outcome in vivo inhibitor innovation metabolic imaging molecular subtypes mouse model neoplastic cell new therapeutic target non-invasive imaging non-invasive monitor novel oligodendroglioma personalized care promoter telomere tumor virtual

6-phosphogluconate Acetoacetates Address Adenine Nucleotides Ascorbic Acid Aspartate Biological Markers Brain Neoplasms Cell Extracts Cell Line Cell Nucleus Cell Proliferation Cell physiology Cells Clinic Data Development Engineering Genetic Glioblastoma Glioma Glucose Glutathione Glutathione Disulfide Goals Image Implant Induced Mutation Lead Link Magnetic Resonance Spectroscopy Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Monitor Mutation NADP Outcome Oxidation-Reduction Oxides Patients Pentosephosphate Pathway Pharmacology Phenotype Process RNA-Directed DNA Polymerase Reaction Reactive Oxygen Species Recurrence Reporting Research Reverse Transcriptase Inhibitors Role Signal Pathway Small Interfering RNA Somatic Cell Telomerase Telomerase inhibition Testing Therapeutic Treatment Efficacy Treatment outcome base beta-Hydroxybutyrate brain parenchyma cancer cell care outcomes drug development genetically modified cells imaging approach imaging biomarker imaging modality improved improved outcome in vivo inhibitor innovation metabolic imaging molecular subtypes mouse model neoplastic cell new therapeutic target non-invasive imaging non-invasive monitor novel oligodendroglioma personalized care promoter telomere tumor virtual

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项目摘要

ABSTRACT Telomerase reverse transcriptase (TERT) enables telomere elongation that is essential for continuous cell proliferation. TERT expression that is associated with activating mutations in the TERT promoter, is observed in virtually all glioblastoma and oligodendroglioma cases. This makes TERT the most common genetic alteration in brain tumors, and a novel therapeutic target. Noninvasive imaging of TERT expression could therefore help in distinguishing between pseudo-progression and recurrent glioma, and provide a noninvasive biomarker for assessment of treatment efficacy by TERT inhibitors. However, to date, no translational imaging approaches for TERT expression have been reported. The goal of Project 3 is to address this critical need by developing metabolic imaging biomarkers of TERT expression. Our approach is based on previous reports showing that TERT expression is associated with control of cellular redox, and our preliminary data confirming this finding and identifying additional metabolic alterations. Specifically, we have found that 1H magnetic resonance spectroscopy (MRS)-detectable levels of glutathione and the 13C MRS-detectable metabolism of hyperpolarized dehydroxyascorbate to vitamin C, are elevated in TERT-expressing cells. Additionally, hyperpolarized 13C MRS- detectable fluxes of glucose and gluconolactone via the pentose phosphate pathway to 6-phosphogluconate are elevated, as are the levels of aspartate and adenosine phosphates. We therefore hypothesize that advanced MRS metabolic imaging could be used to distinguish glioma cells expressing TERT from normal brain parenchyma and from tumor cells in which TERT expression is silenced by treatment. We will test this hypothesis as follows. In Aim 1 we will identify 1H MRS and hyperpolarized 13C MRS metabolic imaging biomarkers that are associated with TERT expression by investigating cell lines that differ only in their TERT status and determining if levels of MRS-detectable metabolic biomarkers associated with redox, and other metabolic changes can distinguish TERT-expressing from TERT non-expressing cells. In Aim 2 we will determine whether MRS- detectable biomarkers of redox can be used to monitor TERT expression in vivo by using mouse models with orthotopic TERT-expressing brain tumors, inhibiting TERT expression via genetic and/or pharmacological approaches, and determining if this inhibition can be assessed using 1H and/or hyperpolarized 13C MRS biomarkers of redox. If cell studies show that other metabolic pathways are modulated by TERT, these will also be investigated in vivo. In Aim 3 we will investigate mechanisms linking TERT expression with metabolism by assessing cellular processes known to be associated with TERT expression and determining if these processes are mechanistically linked to changes in redox-associated metabolic pathways or other MRS-detectable metabolic pathways altered by TERT. Our study is expected to lead to translatable MRS-detectable metabolic biomarkers of TERT expression that could improve glioma patient treatment and outcome.

抽象的端粒酶逆转录酶（TERT）实现端粒伸长，这对于连续细胞至关重要增殖。与TERT启动子中激活突变有关的TERT表达在实际上，所有胶质母细胞瘤和少突胶质瘤病例。这使得tert是最常见的遗传改变在脑肿瘤和一种新型的治疗靶点中。因此，TERT表达的无创成像可能有助于在区分伪产生和复发性神经胶质瘤时，并为无创的生物标志物提供评估TERT抑制剂的治疗功效。但是，迄今为止，没有翻译成像的方法 TERT表达已报道。项目3的目标是通过发展来满足这一关键需求 TERT表达的代谢成像生物标志物。我们的方法基于以前的报告表明 TERT表达与控制细胞氧化还原的控制有关，我们的初步数据证实了这一发现和确定其他代谢改变。具体而言，我们发现1H磁共振光谱法（MRS） - 可检测水平的谷胱甘肽和13c MRS MRS可检测的超极化代谢在表达TERT的细胞中，脱羟基甲酸盐至维生素C升高。此外，超极化13C MRS- 通过磷酸五磷酸五磷酸到6-磷酸葡萄糖酸盐的葡萄糖和葡萄糖醛酮的可检测通量为升高，天冬氨酸和腺苷磷酸盐的水平也是如此。因此，我们假设先进 MRS代谢成像可用于区分正常脑表达TERT的神经胶质瘤细胞实质和肿瘤细胞，其中TERT表达被治疗沉默。我们将检验这个假设如下。在AIM 1中，我们将确定1H MRS和超极化13C MRS代谢成像生物标志物为通过研究仅在其TERT状态上不同并确定的细胞系来与TERT表达相关如果与氧化还原和其他代谢变化相关的MRS可检测代谢生物标志物的水平可以区分表达TERT的非表达细胞。在AIM 2中，我们将确定MRS-是否可检测的氧化还原的生物标志物可用于通过使用带有鼠标的鼠标模型来监视TERT表达原位表达TERT的脑肿瘤，通过遗传和/或药理抑制TERT表达方法，并确定是否可以使用1H和/或超极化13C MRS评估这种抑制作用氧化还原的生物标志物。如果细胞研究表明其他代谢途径是通过TERT调节的，则这些途径也将在体内进行调查。在AIM 3中，我们将研究将TERT表达与代谢联系起来的机制评估已知与TERT表达相关的细胞过程，并确定这些过程是否存在与机械学与氧化还原相关的代谢途径的变化或其他MRS可检测代谢途径通过TERT改变。我们的研究预计将导致可翻译的MRS可检测代谢 TERT表达的生物标志物可以改善神经胶质瘤患者的治疗和预后。