Regulation of Amino-acid Transport in Human Gliomas

人类神经胶质瘤中氨基酸运输的调节

基本信息

批准号：
10520044
负责人：
HARALD W SONTHEIMER
金额：
$ 36.2万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10520044
关键词：
Amino Acids Antioxidants Apoptosis Binding Binding Sites Biological Biological Assay Biological Availability Biology Blood Vessels Brain CD44 Antigens CD44 gene Catalytic Domain Cells Chemotherapy and/or radiation Clinical Clinical Research Clinical Trials Cystine Cytoprotection DNA Binding Domain Data Diagnosis Dideoxy Chain Termination DNA Sequencing Disease Drug Kinetics Edema Extracellular Matrix Free Radicals Functional disorder Future Genes Genetic Genetic Transcription Glioma Glutamates Glutathione Growth Human Hyaluronan Hyaluronic Acid Institutional Review Boards Invaded Iron Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of ovary Measures Mediating Membrane Mutate Mutation Patients Phenotype Physiological Pilot Projects Predictive Value Production Radiation Regulation Resistance Role Seizures Slice Small Interfering RNA Specificity Subgroup System TP53 gene Testing Tetanus Helper Peptide Tissues Transcriptional Regulation Tumor Cell Invasion Tumor Tissue Viral Western Blotting chromatin immunoprecipitation clinically relevant excitotoxicity in vivo inhibitor knock-down mutant mutational status novel overexpression personalized medicine pharmacologic prevent promoter prospective receptor restoration small hairpin RNA stem cells stressor tumor tumor growth uptake

项目摘要

Project Summary/Abstract Glutamate (Glu) has emerged as an important molecule in the biology of malignant brain tumors, specifically gliomas1. Glu can reach toxic concentrations in peritumoral tissue, contributing to enhanced tumor growth and invasion, as well as peritumoral edema, excitotoxicity, and seizures2. Mediated by the cystine-glutamate exchanger, System xc- (SXC), Glu uptake supplies cystine for production of the intracellular antioxidant glutathione (GSH). GSH protects cells from endogenous and exogenous stressors3, including radiation and chemotherapy. GSH over-production confers resistance to radiation4-6 and ferroptosis7, an iron-dependent form of programmed cell death. In previous studies, we show that xCT, the catalytic subunit of SXC, is variably expressed among glioma patients8. Approximately half of tumors show elevated xCT expression and present with seizures and Glu excitotoxicity, whereas gliomas with low xCT expression do not. Similarly, in a clinical pilot study, we show that pharmacological inhibition of SXC reduces Glu release only in gliomas with elevated xCT expression8. Based on recent, data we now hypothesize that differences in the expression and function of SXC are due to its transcriptional and co-receptor regulation. We hypothesize that xCT is transcriptionally regulated by p53, with wild type p53 acting as transcriptional suppressor. As p53 is mutated or deleted in many gliomas, this alteration would result in aberrant overexpression of xCT, explaining the observed Glu release and downstream pathophysiology. We also hypothesize, based on preliminary findings, that the activity of SXC is regulated by extracellular matrix components activating the hyaluronic acid receptor CD44, which serves as a functional co-receptor for SXC. Both p53 and CD44 activity can alter glioma biology and determine peritumoral excitotoxicity, seizures, invasion, and growth. The proposed studies are significant and clinically relevant as they explore new strategies to interfere with the abnormal glutamate biology of gliomas at a transcription and expression level. This proposal provides superior strategies to currently available pharmacological inhibitors for SXC, which have poor specificity and bioavailability. Moreover, the expression of p53 and CD44 may have predictive value regarding potential personalized treatments for this subgroup of glioma in the future.

项目概要/摘要谷氨酸 (Glu) 已成为恶性脑肿瘤生物学中的重要分子，特别是神经胶质瘤1.谷氨酸在肿瘤周围组织中可以达到有毒浓度，有助于促进肿瘤生长和侵袭，以及瘤周水肿、兴奋性毒性和癫痫发作2。由胱氨酸-谷氨酸介导交换器，系统 xc- (SXC)，Glu 摄取提供胱氨酸以产生细胞内抗氧化剂谷胱甘肽（GSH）。 GSH 保护细胞免受内源性和外源性应激源的影响，包括辐射和化疗。 GSH 过量产生可抵抗辐射 4-6 和铁死亡 7（一种铁依赖性形式）程序性细胞死亡。在之前的研究中，我们表明 xCT（SXC 的催化亚基）在不同程度上存在在神经胶质瘤患者中表达8。大约一半的肿瘤显示 xCT 表达升高并存在具有癫痫发作和 Glu 兴奋性毒性，而 xCT 表达低的神经胶质瘤则没有。同样，在临床试验中研究表明，SXC 的药理学抑制仅在 xCT 升高的神经胶质瘤中减少 Glu 释放表达式8.根据最近的数据，我们现在假设 SXC 的表达和功能存在差异这是由于其转录和辅助受体调节。我们假设 xCT 是转录调控的由 p53 控制，野生型 p53 充当转录抑制因子。由于p53在许多神经胶质瘤中发生突变或缺失，这种改变会导致 xCT 异常过度表达，解释了观察到的 Glu 释放和下游病理生理学。根据初步调查结果，我们还假设 SXC 的活动是受激活透明质酸受体 CD44 的细胞外基质成分调节，该受体充当 SXC 的功能性辅助受体。 p53 和 CD44 活性均可改变神经胶质瘤生物学并决定瘤周兴奋性毒性、癫痫发作、侵袭和生长。拟议的研究具有重要意义和临床相关性，因为它们探索干扰神经胶质瘤转录和异常谷氨酸生物学的新策略表达水平。该提案为目前可用的药物抑制剂提供了更好的策略 SXC的特异性和生物利用度较差。此外，p53和CD44的表达可能具有关于未来该胶质瘤亚组潜在个性化治疗的预测价值。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Using Zebrafish to Elucidate Glial-Vascular Interactions During CNS Development.

DOI：
10.3389/fcell.2021.654338
发表时间：
2021
期刊：
Frontiers in cell and developmental biology
影响因子：
5.5
作者：
Umans RA;Pollock C;Mills WA 3rd;Clark KC;Pan YA;Sontheimer H
通讯作者：
Sontheimer H

Perineuronal Net Dynamics in the Pathophysiology of Epilepsy.

DOI：
10.1177/15357597211018688
发表时间：
2021-07
期刊：
Epilepsy currents
影响因子：
3.6
作者：
Chaunsali L;Tewari BP;Sontheimer H
通讯作者：
Sontheimer H

3D Printed Multiplexed Competitive Migration Assays with Spatially Programmable Release Sources.

DOI：
10.1002/adbi.201900225
发表时间：
2020-01
期刊：
Advanced biosystems
影响因子：
4.1
作者：
Haring AP;Thompson EG;Hernandez RD;Laheri S;Harrigan ME;Lear T;Sontheimer H;Johnson BN
通讯作者：
Johnson BN

Astrocyte plasticity in mice ensures continued endfoot coverage of cerebral blood vessels following injury and declines with age.

DOI：
10.1038/s41467-022-29475-2
发表时间：
2022-04-04
期刊：
Nature communications
影响因子：
16.6
作者：
Mills WA 3rd;Woo AM;Jiang S;Martin J;Surendran D;Bergstresser M;Kimbrough IF;Eyo UB;Sofroniew MV;Sontheimer H
通讯作者：
Sontheimer H

Neuroscience: The New English Major?

神经科学：新英语专业？

DOI：
10.1177/10738584211003992
发表时间：
2023
期刊：
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
影响因子：
0
作者：
Phillips,KristinF;Sontheimer,Harald
通讯作者：
Sontheimer,Harald