Metabolic aberrations in glioma initiation

神经胶质瘤发生过程中的代谢异常

• 批准号: 9002102
• 负责人: Thomas A Neubert
• 金额: $ 8.48万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9002102
• 关键词: Address; Adipocytes; Affect; Animals; Area; Arginine; Astrocytes; Behavior; Biology; Brain; Brain Neoplasms; Catalytic Domain; Cell Proliferation; Cell physiology; Cells; Cellular Metabolic Process; Cessation of life; Characteristics; Clinical; DNA Methylation; Detection; Deterioration; Development; Disease model; Early Diagnosis; Enchondromatosis; Enzymes; Epigenetic Process; Event; Excision; Experimental Models; Fluorescence; Future; Genes; Genetic Engineering; Genetically Engineered Mouse; Germ-Line Mutation; Glioma; Gliomagenesis; Health; Histidine; Horns; Human; Imagery; Immunocompromised Host; Implant; In Vitro; Incidence; Infiltration; Investigation; Isocitrate Dehydrogenase; Isocitrates; Lead; Maffucci Syndrome; Magnetic Resonance Imaging; Maintenance; Mass Spectrum Analysis; Metabolic; Metabolism; Methods; Modeling; Modification; Monitor; Mus; Mutate; Mutation; Myeloid Cells; Neurologic; Neurons; Oligodendroglia; Oncogenic; Operative Surgical Procedures; Patients; Perinatal; Phase; Phenotype; Positioning Attribute; Preclinical Drug Evaluation; Primary Brain Neoplasms; Production; Proliferating; Protein Isoforms; Reporter; Research; Research Proposals; Role; Staging; Stem cells; Stream; System; Testing; Therapeutic; Time; Transgenic Organisms; Transplantation; Up-Regulation; Variant; Work; alpha ketoglutarate; base; biomarker identification; brain cell; brain tissue; cell type; epigenome; frontal lobe; gain of function; gain of function mutation; genome-wide; histological image; histone methylation; human embryonic stem cell; human embryonic stem cell line; improved; in vivo; inducible gene expression; lateral ventricle; metabolome; mouse model; mutant; nerve stem cell; neuroblast; neurogenesis; novel strategies; novel therapeutics; outcome forecast; phosphoproteomics; relating to nervous system; research study; self-renewal; subventricular zone; transcriptome; transcriptome sequencing; translational study; tumor; tumor initiation; tumor xenograft; tumorigenesis; ventricular system; young adult

 DESCRIPTION (provided by applicant): Low-grade gliomas (LGGs) are primary brain tumors affecting young adults. Although they initially grow relatively slowly, they eventually transform t more aggressive high-grade gliomas, leading to neurologic deterioration and death. The questions of cell of origin and significance of known mutations in early low-grade gliomagenesis remain unanswered, thus limiting the ability to develop sensitive detection methods and new therapies. In up to 80% of LGGs, gain-of-function mutations are found in the gene encoding the cytosolic isoform of Isocitrate DeHydrogenase (IDH), usually due to an arginine to histidine substitution at position 132 (R132H). While the wild-type enzyme normally functions to convert isocitrate to a-ketoglutarate (aKG), R132H-IDH1 catalyzes the production of R-2-hydroxyglutarate (2HG), which leads to genome-wide epigenetic modifications that may be related to tumorigenesis. The putative role of IDH1 mutations in gliomagenesis has been supported by in vitro observations in human astrocytes and glioma cells, as well as the fact that patients with Ollier disease, which is due to mosaic germline mutations of IDH1, occasionally develop gliomas. LGGs bearing IDH1 mutations are predominantly located in the frontal lobes in close proximity to the frontal horns of the ventricular system. Because the subventricular zone around the lateral ventricles is an area of active neurogenesis, we postulate that the cell of origin in IDH1-mutated LGGs is a component of the neurogenic niche in the subventricular zone. Mouse models of brain-specific mutant IDH1 expression suffer from perinatal lethality and fail to show tumorigenesis. To test the hypothesis that mutant IDH1 represents a "driver" alteration in LGG initiation and to investigate which brain cells are predisposed by mutant IDH1 to undergo oncogenic transformation, we propose a new approach that overcomes limitations associated with in vitro and in vivo mouse models. Our strategy makes use of human embryonic stem cells to inducibly express R132H-IDH1 in specific cell types within the human neural lineage: neural stem cells, neuroblasts, astrocytes and oligodendrocytes. We propose to test the hypothesis that inducible expression of R132H-IDH1 alters the self-renewal, differentiation potential, proliferation rate, metabolome and epigenetic/transcriptional profile of neural stem cells or other components of the human neural lineage in vitro. Furthermore, to test the hypothesis that mutant IDH1 expression in specific human neural cell types contributes to initiation of LGG formation, we will transplant these target cells expressing R132H-IDH1 into the mouse brain and assess their ability to form invasive tumors. The proposed research will address the important question of whether IDH1 mutations in human embryonic stem cell-derived neural lineages alter cellular physiology and facilitate oncogenic transformation. Successful completion of this project will lead to a disease model, which will allow detailed analysis of the metabolome, epigenome and transcriptome of early human LGGs. Furthermore, such a model can be used for translational applications, such as high-throughput drug screening and biomarker identification.

 描述（由申请人提供）：低级别胶质瘤（LGG）是影响年轻人的原发性脑肿瘤。虽然它们最初生长相对缓慢，但它们最终转化为更具侵略性的高级别胶质瘤，导致神经功能恶化和死亡。细胞起源和早期低级别胶质瘤发生中已知突变的意义的问题仍然没有答案，从而限制了开发灵敏的检测方法和新疗法的能力。在高达80%的LGG中，在编码异柠檬酸脱氢酶（IDH）的胞质同种型的基因中发现了功能获得性突变，通常是由于132位（R132 H）的精氨酸取代为组氨酸。虽然野生型酶通常用于将异柠檬酸转化为α-酮戊二酸（aKG），但R132 H-IDH 1催化R-2-羟基戊二酸（2 HG）的产生，这导致可能与肿瘤发生相关的全基因组表观遗传修饰。IDH 1突变在胶质瘤发生中的假定作用得到了人星形胶质细胞和胶质瘤细胞体外观察的支持，以及由于IDH 1的嵌合生殖系突变导致的Ollier病患者偶尔会发展为胶质瘤的事实。携带IDH 1突变的LGG主要位于额叶中，紧邻脑室系统的前角。由于侧脑室周围的脑室下区是一个活跃的神经发生的区域，我们假设，在IDH 1突变LGG的起源细胞是脑室下区的神经原性生态位的一个组成部分。脑特异性突变体IDH 1表达的小鼠模型遭受围产期致死性并且未能显示肿瘤发生。为了验证突变IDH 1代表LGG启动中的“驱动”改变的假设，并研究哪些脑细胞易受突变IDH 1的影响而发生致癌转化，我们提出了一种新的方法，该方法克服了与体外和体内小鼠模型相关的限制。我们的策略利用人胚胎干细胞在人神经谱系内的特定细胞类型中诱导表达R132 H-IDH 1：神经干细胞、神经母细胞、星形胶质细胞和少突胶质细胞。我们建议测试的假设，诱导表达的R132 H-IDH 1改变自我更新，分化潜能，增殖率，代谢组和表观遗传/转录谱的神经干细胞或其他组成部分的人神经谱系在体外。此外，为了检验突变IDH 1在特定人类神经细胞类型中的表达有助于LGG形成的启动的假设，我们将这些表达R132 H-IDH 1的靶细胞移植到小鼠脑中，并评估它们形成侵袭性肿瘤的能力。拟议的研究将解决人类胚胎干细胞衍生的神经谱系中IDH 1突变是否会改变细胞生理学并促进致癌转化的重要问题。该项目的成功完成将导致疾病模型，这将允许对早期人类LGG的代谢组，表观基因组和转录组进行详细分析。此外，这种模型可以用于翻译应用，例如高通量药物筛选和生物标志物鉴定。

项目成果

Patient-Specific Screening Using High-Grade Glioma Explants to Determine Potential Radiosensitization by a TGF-β Small Molecule Inhibitor.

• DOI: 10.1016/j.neo.2016.08.008
• 发表时间: 2016-12
• 期刊: NEOPLASIA
• 影响因子: 4.8
• 作者: Bayin, N. Sumru;Ma, Lin;Thomas, Cheddhi;Baitalmal, Rabaa;Sure, Akhila;Fansiwala, Kush;Bustoros, Mark;Golfinos, John G.;Pacione, Donato;Snuderl, Matija;Zagzag, David;Barcellos-Hoff, Mary Helen;Placantonakis, Dimitris
• 通讯作者: Placantonakis, Dimitris

MR imaging phenotype correlates with extent of genome-wide copy number abundance in IDH mutant gliomas.

• DOI: 10.1007/s00234-019-02219-8
• 发表时间: 2019-09
• 期刊: Neuroradiology
• 影响因子: 2.8
• 作者: Wu CC;Jain R;Neto L;Patel S;Poisson LM;Serrano J;Ng V;Patel SH;Placantonakis DG;Zagzag D;Golfinos J;Chi AS;Snuderl M
• 通讯作者: Snuderl M

Modeling HSV-1 Latency in Human Embryonic Stem Cell-Derived Neurons.

• DOI: 10.3390/pathogens6020024
• 发表时间: 2017-06-08
• 期刊: Pathogens (Basel, Switzerland)
• 作者: Pourchet A;Modrek AS;Placantonakis DG;Mohr I;Wilson AC
• 通讯作者: Wilson AC