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

基本信息

批准号：
9131426
负责人：
HARALD W SONTHEIMER
金额：
$ 35.22万
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：
2015
资助国家：
美国
起止时间：
2015-08-22 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9131426
关键词：
Acute Address Amino Acids Animals Antiepileptic Agents Antioxidants Astrocytes Biochemical Biopsy Brain Brain region Catabolism Cell Death Cells Child Chronic Clinical Clinical Treatment Comorbidity Complement Cysteine Cystine Development Diagnosis Drug Targeting Electroencephalography Environment Enzymes Epilepsy Equilibrium Etiology Evidence based intervention FDA approved Funding GABA Receptor Glioma Glutamate Receptor Glutamate Transporter Glutamate-Ammonia Ligase Glutamates Goals Grant High Pressure Liquid Chromatography Human Human Biology Image Intractable Headaches Invaded Link Malignant neoplasm of brain Mass Spectrum Analysis Microglia Modeling Molecular Monitor Mus Nature Neurons Neurotransmitter Receptor Optics Oxidation-Reduction Patients Pharmaceutical Preparations Phase I Clinical Trials Phenotype Play Primary Brain Neoplasms Proteins Receptor Activation Recruitment Activity Refractory Relative (related person)Research Resistance Role Sampling Seizures Severities Slice Sulfasalazine Symptoms System Talampanel Time Tissues Translations Tumor Tissue Western Blotting Work Xenograft procedure base cysteinylcysteine expectation glutamyl-glutamic acid in vivo inhibitor/antagonist insight macrophage neoplastic cell neuronal excitability novel patch clamp protein expression receptor reuptake small hairpin RNA transmission process tumor tumor growth uptake voltage

项目摘要

DESCRIPTION (provided by applicant): Glioma is the most common and deadly primary brain tumor. For many patients intractable headaches and epileptic seizures are early symptoms. Seizures arise from tumor associated "peritumoral" brain and are particularly common in low grade gliomas where up to 90% of patients present with spontaneous recurring seizures, or "peritumoral epilepsy" that is often refractory to treatment. The central hypothesis developed during the previous funding cycle of this grant posits that seizures are caused by the deliberate release of glutamate from gliomas into the peritumoral brain, causing abnormal neuronal glutamate receptor activation, and, over time, glutamate causes tumor associated brain regions to become hyperexcitable. It is hypothesized that glutamate is released as an obligatory by-product of cystine uptake into tumor cells via the system xc- (SXC) cystine-glutamate exchanger. In addition, the tumor may co-opt adjacent astrocytes or recruit microglial cells to release glutamate. Whether and how glutamate release from either of these cells is mechanistically involved in seizure initiation is the principle question of this proposal. This question will be addressed by comparing the seizure phenotype of tumor bearing mice generated from human xenografts with high or low SXC expression, shRNA silencing or pharmacological inhibition. The time-course of seizure development will be documented by EEG/video monitoring with the expectation that reduced SXC expression delays seizure onset and reduces seizure severity. To study cellular changes underlying the neuronal hyperexcitability, including neurotransmitter receptor and transporter expression and function, acute brain slices from animals with known seizure status will be studied biophysically. These results will be complemented by biochemical and immunohistochemical analysis of biopsies and tissue micro arrays from over 300 human glioma patients to search for changes in proteins involved in glutamate release, reuptake or catabolism. If a role for glutamate in seizure initiatio is confirmed, the availability of two FDA approved drugs, Sulfasalazine and Talampanel that inhibit either glutamate release or glutamate receptors should allow for a rapid translation towards clinical treatment of patients. Previous glioma research has almost exclusively focused on high grade gliomas and hence a novel objective of this study is a focus on a more effective management of peritumoral seizures in low grade gliomas, which present a significant clinical challenge.

描述（由申请人提供）：神经胶质瘤是最常见和致命的原发性脑肿瘤。对于许多患者来说，顽固性头痛和癫痫发作是早期症状。癫痫发作由肿瘤相关的“瘤周”大脑引起，在低度恶性胶质瘤中尤其常见，其中高达 90% 的患者出现自发性复发性癫痫发作，或通常难以治疗的“瘤周癫痫”。在本次资助的上一个资助周期中提出的中心假设认为，癫痫发作是由于神经胶质瘤故意将谷氨酸释放到瘤周大脑中引起的，导致神经元谷氨酸受体激活异常，并且随着时间的推移，谷氨酸会导致与肿瘤相关的大脑区域变得异常。过度兴奋。据推测，谷氨酸作为胱氨酸通过系统 xc-(SXC) 胱氨酸-谷氨酸交换器摄取到肿瘤细胞中的必然副产物而释放。此外，肿瘤可能会选择邻近的星形胶质细胞或招募小胶质细胞来释放谷氨酸。这些细胞中的任何一个的谷氨酸释放是否以及如何在机制上参与癫痫发作是该提案的主要问题。这个问题将通过比较具有高或低 SXC 表达、shRNA 沉默或药理抑制的人类异种移植物产生的荷瘤小鼠的癫痫表型来解决。癫痫发作的时间进程将通过脑电图/视频监测记录，预计 SXC 表达的减少会延迟癫痫发作并降低癫痫发作的严重程度。为了研究神经元过度兴奋背后的细胞变化，包括神经递质受体和转运蛋白的表达和功能，将对来自已知癫痫状态的动物的急性脑切片进行生物物理学研究。这些结果将通过对 300 多名人类神经胶质瘤患者的活检和组织微阵列进行生化和免疫组织化学分析来补充，以寻找与谷氨酸释放、再摄取或分解代谢相关的蛋白质的变化。如果谷氨酸在癫痫发作中的作用得到证实，那么两种 FDA 批准的抑制谷氨酸释放或谷氨酸受体的药物柳氮磺胺吡啶和 Talampanel 的可用性应该可以快速转化为患者的临床治疗。以前的神经胶质瘤研究几乎完全集中于高级别神经胶质瘤，因此本研究的一个新目标是关注更有效地管理低级别神经胶质瘤的瘤周癫痫发作，这提出了重大的临床挑战。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glutamate and the biology of gliomas.

DOI：
10.1002/glia.21113
发表时间：
2011-08
期刊：
GLIA
影响因子：
6.2
作者：
de Groot, John;Sontheimer, Harald
通讯作者：
Sontheimer, Harald

Sulfasalazine for brain cancer fits.

DOI：
10.1517/13543784.2012.670634
发表时间：
2012-05
期刊：
Expert opinion on investigational drugs
影响因子：
6.1
作者：
Sontheimer H;Bridges RJ
通讯作者：
Bridges RJ

Erythropoietin-induced neuroprotection requires cystine glutamate exchanger activity.

促红细胞生成素诱导的神经保护需要胱氨酸谷氨酸交换活性。

DOI：
10.1016/j.brainres.2010.01.040
发表时间：
2010
期刊：
Brain research
影响因子：
2.9
作者：
Sims,Brian;Clarke,Melinda;Njah,Wilfred;Hopkins,E'lanaShuford;Sontheimer,Harald
通讯作者：
Sontheimer,Harald

Glutamate and tumor-associated epilepsy.

DOI：
10.18632/oncotarget.350
发表时间：
2011-11
期刊：
Oncotarget
影响因子：
0
作者：
Sontheimer H
通讯作者：
Sontheimer H

Inhibition of System Xc(-) Transporter Attenuates Autoimmune Inflammatory Demyelination.

DOI：
10.4049/jimmunol.1401108
发表时间：
2015-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Evonuk KS;Baker BJ;Doyle RE;Moseley CE;Sestero CM;Johnston BP;De Sarno P;Tang A;Gembitsky I;Hewett SJ;Weaver CT;Raman C;DeSilva TM
通讯作者：
DeSilva TM