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:10321925
- 负责人:
- 金额:$ 36.2万
- 依托单位:
- 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 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:Amino AcidsAntioxidantsApoptosisBindingBinding SitesBiologicalBiological AssayBiological AvailabilityBiologyBlood VesselsBrainCD44 AntigensCD44 geneCatalytic DomainCellsChemotherapy and/or radiationClinicalClinical ResearchClinical TrialsCystineDNA Binding DomainDataDiagnosisDideoxy Chain Termination DNA SequencingDiseaseDrug KineticsEdemaExtracellular MatrixFree RadicalsFunctional disorderFutureGenesGeneticGenetic TranscriptionGliomaGlutamatesGlutathioneGrowthHumanHyaluronanHyaluronic AcidInstitutional Review BoardsIronMalignant NeoplasmsMalignant neoplasm of brainMalignant neoplasm of ovaryMeasuresMediatingMembraneMutateMutationPatientsPharmacologyPhenotypePhysiologicalPilot ProjectsPredictive ValueProductionRegulationResistanceRoleSeizuresSliceSmall Interfering RNASpecificitySubgroupSystemTP53 geneTestingTetanus Helper PeptideTissuesTranscriptional RegulationTumor Cell InvasionViralWestern Blottingbasechromatin immunoprecipitationclinically relevantexcitotoxicityin vivoinhibitorknock-downmutantmutational statusnoveloverexpressionpersonalized medicinepreventpromoterprospectivereceptorrestorationsmall hairpin RNAstem cellstumortumor growthuptake
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.
项目摘要/摘要
谷氨酸(Glu)已成为恶性脑肿瘤生物学中的重要分子,尤其是
胶质瘤1。谷氨酸可在肿瘤周围组织中达到有毒浓度,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2。由半胱氨酸-谷氨酸介导
交换系统XC-(SXC),Glu摄取为细胞内抗氧化剂的生产提供半胱氨酸
谷胱甘肽(GSH)GSH保护细胞免受内源性和外源性压力,包括辐射和
化疗。GSH的过量生产使人对辐射4-6和铁中毒7具有抵抗力,这是一种依赖铁的形式
程序性细胞死亡。在以前的研究中,我们证明了SXC的催化亚基XCT是可变的
在胶质瘤患者中表达。大约一半的肿瘤显示XCT表达升高并存在
与癫痫发作和谷氨酸兴奋毒性有关,而XCT低表达的胶质瘤则没有。同样,在一项临床试验中
研究表明,SXC的药理抑制只在XCT升高的胶质瘤中减少Glu的释放
表情8。根据最近的数据,我们现在假设SXC的表达和功能的差异
是由于它的转录和共同受体的调节。我们假设XCT是转录调控的
P53,野生型P53作为转录抑制因子。由于P53在许多胶质瘤中发生突变或缺失,
这种改变会导致XCT的异常过表达,解释了观察到的Glu释放和
下游的病理生理学。我们还假设,根据初步发现,SXC的活性是
由激活透明质酸受体CD44的细胞外基质成分调节,CD44作为一种
SXC的功能性共受体。P53和CD44活性均可改变胶质瘤生物学行为并确定瘤周
兴奋性毒性、癫痫发作、入侵和生长。拟议的研究具有重要意义和临床意义,因为它们
探索在转录和转录水平干扰脑胶质瘤谷氨酸异常生物学的新策略
表达式级别。这一建议提供了优于目前可用的药物抑制剂的策略
SXC的特异性和生物利用度较差。此外,P53和CD44的表达可能有
对未来这一亚组胶质瘤的潜在个体化治疗的预测价值。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
HARALD W SONTHEIMER其他文献
HARALD W SONTHEIMER的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('HARALD W SONTHEIMER', 18)}}的其他基金
Changes in Cerebrovascular Function with Aging in Normal and AD Brain
正常脑和 AD 脑中脑血管功能随衰老的变化
- 批准号:
10543141 - 财政年份:2020
- 资助金额:
$ 36.2万 - 项目类别:
Changes in Cerebrovascular Function with Aging in Normal and AD Brain
正常脑和 AD 脑中脑血管功能随衰老的变化
- 批准号:
10334548 - 财政年份:2020
- 资助金额:
$ 36.2万 - 项目类别:
Changes in Cerebrovascular Function with Aging in Normal and AD Brain
正常脑和 AD 脑中脑血管功能随衰老的变化
- 批准号:
10438950 - 财政年份:2020
- 资助金额:
$ 36.2万 - 项目类别:
Regulation of Amino-acid Transport in Human Gliomas
人类神经胶质瘤中氨基酸运输的调节
- 批准号:
10393364 - 财政年份:2018
- 资助金额:
$ 36.2万 - 项目类别:
Regulation of Amino-acid Transport in Human Gliomas
人类神经胶质瘤中氨基酸运输的调节
- 批准号:
10064133 - 财政年份:2018
- 资助金额:
$ 36.2万 - 项目类别:
Regulation of Amino-acid Transport in Human Gliomas
人类神经胶质瘤中氨基酸运输的调节
- 批准号:
10520044 - 财政年份:2018
- 资助金额:
$ 36.2万 - 项目类别:
Amino Acid Transport and the Biology of Human Gliomas
氨基酸转运和人类神经胶质瘤的生物学
- 批准号:
9131426 - 财政年份:2015
- 资助金额:
$ 36.2万 - 项目类别:
相似海外基金
Enhancing gamete cryoprotective properties of graphene oxide by dual functionalization with antioxidants and non-penetrating cryoprotectant molecules
通过抗氧化剂和非渗透性冷冻保护剂分子的双重功能化增强氧化石墨烯的配子冷冻保护特性
- 批准号:
24K18002 - 财政年份:2024
- 资助金额:
$ 36.2万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
SBIR Phase I: Sustainable antioxidants for industrial process fluids
SBIR 第一阶段:工业过程流体的可持续抗氧化剂
- 批准号:
2222215 - 财政年份:2023
- 资助金额:
$ 36.2万 - 项目类别:
Standard Grant
Development of a new bone augmentation method that enables long-term survival and long-term functional expression of transplanted cells by antioxidants
开发一种新的骨增强方法,通过抗氧化剂使移植细胞能够长期存活和长期功能表达
- 批准号:
23K09272 - 财政年份:2023
- 资助金额:
$ 36.2万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Non-Invasive Probing Cellular Oxidative Stress and Antioxidants Therapeutic Effectiveness
非侵入性探测细胞氧化应激和抗氧化剂的治疗效果
- 批准号:
10652764 - 财政年份:2023
- 资助金额:
$ 36.2万 - 项目类别:
Mitochondria-targeting Novel Cationic Hydrazone Antioxidants for the Treatment of Preeclampsia
线粒体靶向新型阳离子腙抗氧化剂用于治疗先兆子痫
- 批准号:
10730652 - 财政年份:2023
- 资助金额:
$ 36.2万 - 项目类别:
Effects of different doses of antioxidants(Vitamin E) intake on exercise induced oxidative stress, antioxidative capacity and chronic inflammation
不同剂量抗氧化剂(维生素E)摄入对运动引起的氧化应激、抗氧化能力和慢性炎症的影响
- 批准号:
22K11609 - 财政年份:2022
- 资助金额:
$ 36.2万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Contribution of antioxidants to regeneration of rotator cuff insertion
抗氧化剂对肩袖插入再生的贡献
- 批准号:
22K16720 - 财政年份:2022
- 资助金额:
$ 36.2万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Latent Antioxidants for Environmentally Responsible Polymer Formulations
用于环保聚合物配方的潜在抗氧化剂
- 批准号:
RGPIN-2018-04107 - 财政年份:2022
- 资助金额:
$ 36.2万 - 项目类别:
Discovery Grants Program - Individual
Polyunsaturated fatty acid (PUFA), inflammation and antioxidants
多不饱和脂肪酸 (PUFA)、炎症和抗氧化剂
- 批准号:
RGPIN-2019-05674 - 财政年份:2022
- 资助金额:
$ 36.2万 - 项目类别:
Discovery Grants Program - Individual
Suppressed methemoglobin formation of artificial red cell by liposomal antioxidants and its mechanism.
脂质体抗氧化剂抑制人工红细胞高铁血红蛋白形成及其机制
- 批准号:
22K12824 - 财政年份:2022
- 资助金额:
$ 36.2万 - 项目类别:
Grant-in-Aid for Scientific Research (C)