Imaging regional gene expression variability in brain tumor associated seizures

脑肿瘤相关癫痫发作的区域基因表达变异成像

• 批准号: 8873267
• 负责人: Jong Woo Lee
• 金额: $ 8.86万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8873267
• 关键词: Adult Glioma; Adverse effects; Affect; Antiepileptic Agents; Area; Benchmarking; Brain; Brain Neoplasms; Brain region; Characteristics; Data; Data Analyses; Data Set; Diagnosis; Epilepsy; Foundations; Gene Expression; Genes; Genomics; Glioma; Glutamate Transporter; Glutamates; Goals; Image; Individual; Lead; Life Expectancy; Linear Models; Link; Location; Magnetic Resonance Imaging; Maps; Methods; Modality; Molecular; Morbidity - disease rate; National Institute of Neurological Disorders and Stroke; Nature; Neoplasms; Outcome; Pathway interactions; Patients; Play; Quality of life; Research; Seizures; System; Temporal Lobe; The Cancer Genome Atlas; Tumor-Associated Process; Validation; Work; cancer imaging; cost; design; differential expression; experience; extracellular; frontal lobe; image archival system; imaging modality; improved; neuroimaging; novel; overexpression; programs; public health relevance; repository; targeted treatment; tool; treatment strategy; tumor

 DESCRIPTION (provided by applicant): Tumor associated seizures (TAS) are present in approximately half of the patients with brain tumors and cause a marked decrease in the quality of life in these patients. Understanding the underlying mechanisms of TAS, crucial in developing new therapies, is hindered by its multifactorial nature, as both imaging and genomic characteristics play key roles. Examining the contribution of neuroimaging and gene expression in TAS in concert will more readily lead to discovery of biologically relevant mechanisms of TAS than by assessment of either modality in isolation. The central hypothesis of this study is that tumor gene expression is associated with TAS in a brain region-specific manner. This study will utilize the genomic and MRI data from carefully curated public repositories: The Cancer Genome Atlas (TCGA), Repository for Molecular BRAin Neoplasia DaTa (REMBRANDT, for validation), and The Cancer Imaging Archive (TCIA). The specific aims are: 1) Using TCGA dataset, identify genes and gene sets that are differentially expressed in patients with versus without TAS. 2) Using TCGA and TCIA datasets, characterize brain regions where gene expression has significant correlation with TAS. Particular focus will be on the expression of SLC7A11 which encodes the system xc- glutamate transporter, which causes a well-established mechanism of TAS through dysregulation of glutamate. The datasets will be assessed for differential expression of other novel genes and gene sets. Newly developed gene expression statistical image mapping tools will be utilized to analyze in what brain region the expression of SLC7A11 and other key genes are significantly associated with TAS, with the hypothesis that SLC7A11 expression have a higher correlation with TAS in the temporal, as compared to the frontal, lobes. Genes that are correlated to TAS because of association with tumor location, but without specific epileptogenic mechanisms, will demonstrate no regions of significance. Incorporating both gene expression and imaging information simultaneously is a novel and powerful method of characterizing TAS. In accordance with the NINDS Benchmarks for Epilepsy Research, completion of this will result in 1) improved identification of tumors that are most likey to respond to anti-glutaminergic treatments, 2) identification of genes and pathways associated with epilepsy; 3) advancement in the understanding of the epileptogenic process of TAS.

 描述（由申请人提供）：大约一半的脑肿瘤患者存在肿瘤相关癫痫发作（TAS），并导致这些患者的生活质量显着下降。了解 TAS 的潜在机制对于开发新疗法至关重要，但由于其多因素性质而受到阻碍，因为成像和基因组特征都发挥着关键作用。与单独评估任一方式相比，共同检查神经影像学和基因表达在 TAS 中的贡献将更容易发现 TAS 的生物学相关机制。这项研究的中心假设是肿瘤基因表达以大脑区域特异性的方式与 TAS 相关。这项研究将利用来自精心策划的公共存储库的基因组和 MRI 数据：癌症基因组图谱 (TCGA)、分子脑肿瘤 DaTa 存储库 (REMBRANDT，用于验证) 和癌症成像档案 (TCIA)。具体目标是：1) 使用 TCGA 数据集，识别在 TAS 患者与非 TAS 患者中差异表达的基因和基因集。 2) 使用 TCGA 和 TCIA 数据集，描述基因表达与 TAS 显着相关的大脑区域。特别关注的是 SLC7A11 的表达，它编码 xc-谷氨酸转运蛋白系统，该系统通过谷氨酸失调导致 TAS 的成熟机制。将评估数据集的其他新基因和基因集的差异表达。新开发的基因表达统计图像映射工具将用于分析SLC7A11和其他关键基因的表达在哪些大脑区域与TAS显着相关，并假设与额叶相比，SLC7A11表达在颞叶与TAS具有更高的相关性。由于与肿瘤位置相关而与 TAS 相关的基因，但没有特定的致癫痫机制，将不会表现出任何重要区域。同时结合基因表达和成像信息是表征 TAS 的一种新颖而强大的方法。根据 NINDS 癫痫研究基准，完成这项工作将导致 1) 改进对最有可能对抗谷氨酰胺能治疗产生反应的肿瘤的识别，2) 识别与癫痫相关的基因和途径； 3）对TAS致癫痫过程的理解取得进展。