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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：
10064133
负责人：
HARALD W SONTHEIMER
金额：
$ 14.02万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
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 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064133
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 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 Iron Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of ovary Measures Mediating Membrane Mutate Mutation Patients Pharmacology Phenotype Physiological Pilot Projects Predictive Value Production Regulation Resistance Role Seizures Slice Small Interfering RNA Specificity Subgroup System TP53 gene Testing Tetanus Helper Peptide Tissues Transcriptional Regulation Tumor Cell Invasion Viral Western Blotting base chromatin immunoprecipitation clinically relevant excitotoxicity in vivo inhibitor/antagonist knock-down mutant mutational status novel overexpression personalized medicine prevent promoter prospective receptor restoration small hairpin RNA stem cells 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.

项目总结/文摘