Polyamine and Glutamate Driven Interactions in the Glioblastoma-Brain Microenvironment

项目摘要 放射治疗是脑损伤的标准治疗方式，并通过以下方式改善了患者的预后 增加了高精度的立体定向递送和最近的粒子治疗。当病人们在 受益于生存时间的增加，认知并发症的发生频率增加，并 因此对治疗模式提出了挑战。电离辐射神经毒性的生物学机制 都不清楚。最近的研究强调了对传统意义上的器官的精致敏感性 由于其非增殖性而被认为是抗辐射的。树突状细胞重塑、神经炎症和 在暴露于电离辐射后，兴奋性毒性都会增加，并被认为是导致 认知能力下降。在目前的应用中，我们认为过度的谷氨酸信号是一个关键的驱动因素 辐射造成的认知损害。此外，我们的小组一直在调查多胺的作用 肿瘤细胞辐射耐受途径。谷氨酸和多胺都被发现在 脑瘤，一种诱导性分泌物，在暴露于辐射后明显。在机械学研究中，我们认为 NMDAR NR2B亚基作为谷氨酸和多胺的特异性靶标，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将 减少辐射对中枢神经系统的损伤，使肿瘤细胞对辐射诱导的死亡敏感，因此 改善患者的预后。

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.