Polyamine and Glutamate Driven Interactions in the Glioblastoma-Brain Microenvironment

胶质母细胞瘤-脑微环境中多胺和谷氨酸驱动的相互作用

基本信息

批准号：
10450174
负责人：
Scott Michael Welford
金额：
$ 34.07万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
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：
2015-08-07 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10450174
关键词：
Adopted Apoptosis Architecture Blood Brain Brain Glioblastoma Brain Injuries Brain Neoplasms CRISPR/Cas technology Cell Death Cells Cessation of life Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cognition Cognitive Cognitive deficits Conformal Radiotherapy Cranial Irradiation DNA Repair Gene Dendrites Disease Dose-Limiting Effectiveness Electrophysiology (science)Electroporation Embryo Enzymes Event Excitatory Amino Acid Antagonists Exposure to Flow Cytometry Frequencies Gene Expression Genetic Models Glioblastoma Glioma Glutamate Metabolism Pathway Glutamate Receptor Glutamates Glutamine Hippocampus (Brain)Hour Immunocompetent Immunotherapy Impaired cognition Ionizing radiation Lead Lesion Link Mediating Mediator of activation protein Modality Modeling Morbidity - disease rate Mus N-Methyl-D-Aspartate Receptors Nature Nervous System Trauma Neuraxis Neurons Neurotransmitters Normal tissue morphology Organ Pathway interactions Patient-Focused Outcomes Patients Pharmacology Phosphorylation Play Polyamines Protons Radiation Radiation Interaction Radiation Tolerance Radiation exposure Radiation induced damage Radiation therapy Radiation-Sensitizing Agents Radiosensitization Receptor Signaling Resistance Roentgen Rays Role Signal Pathway Signal Transduction Slice Specificity Structure System Therapeutic Time Toxic effect Tumor Suppressor Genes adverse outcome autocrine base cell type excitotoxicity extracellular gene therapy genome editing glutamatergic signaling ifenprodil improved improved outcome in utero inhibitor innovation insight irradiation neoplastic cell neuroinflammation neuron loss neurotoxicity neutralizing monoclonal antibodies novel particle therapy preclinical study protective effect radiation resistance radioresistant standard of care therapy resistant tumor tumor growth

项目摘要

Project Summary Radiotherapy is a standard modality for brain lesions, and has led improvements in patient outcome through the addition of high precision stereotactic delivery and more recently particle therapy. While patients are benefiting from increasing survival times, cognitive complications develop with increased frequency and are thus challenging treatment paradigms. Biologically, the mechanisms of neurotoxicity from ionizing radiation are unclear. Recent studies have highlighted exquisite sensitivity to an organ that has been traditionally thought to be radioresistant due to its non-proliferative nature. Dendrite remodeling, neuroinflammation, and excitotoxicity are all elevated following exposure to ionizing radiation, and are thought to contribute to decreased cognition. In the current application, we propose that excessive glutamate signaling is a key driver of cognitive damage from radiation. In addition, our group has been investigating the role of the polyamine pathway in radiation resistance of tumor cells. Both glutamate and polyamines are found to be elevated in brain tumors, an induced secretion is evident after exposure to radiation. In mechanistic studies, we implicate the NMDAR NR2B subunit as a specific target of glutamate and polyamines that leads to neurotoxicity. We hypothesize that blocking glutamate-receptor signaling with a specific glutamate receptor antagonist will reduce CNS damage due to radiation, and sensitize tumor cells to radiation induced death, and therefore improve patient outcomes.

项目摘要放疗是脑损伤的标准方式，并通过添加高精度立体定向递送和最近的粒子疗法。而患者是受益于增加生存时间，认知并发症随频率的增加而发展，并且因此挑战治疗范例。从生物学上讲，神经毒性从电离辐射中的机制不清楚。最近的研究强调了对传统上的器官的精致敏感性由于其非增殖性质而被认为是放射抗性的。树突重塑，神经炎症和暴露于电离辐射后，兴奋性毒性均升高，被认为有助于认知下降。在当前应用中，我们建议过多的谷氨酸信号传导是关键驱动器辐射的认知损害。此外，我们的小组一直在研究多胺的作用肿瘤细胞辐射阻力的途径。发现谷氨酸和多胺均升高暴露于辐射后，脑肿瘤是一种诱发的分泌。在机械研究中，我们暗示 NMDAR NR2B亚基作为谷氨酸和多胺的特定靶标，导致神经毒性。我们假设用特定的谷氨酸受体拮抗剂阻断谷氨酸受体信号传导将减少因辐射引起的中枢神经系统损害，并使肿瘤细胞对辐射诱导的死亡敏感，因此改善患者的预后。