Investigating neuroinflammatory and neuronal mechanisms underlying the adverse neurological effects of brain radiotherapy

研究脑放疗不良神经学影响背后的神经炎症和神经元机制

• 批准号: 2772734
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2772734
• 关键词: Investigating; neuroinflammatory; neuronal; mechanisms; underlying

Glioblastoma (GBM) is the most commonly occurring primary brain tumour and is a cancer of extreme unmet need. While clinical outcomes remain poor, overall survival has risen over the past 20 years, revealing the devastating impact of treatment-associated neurological complications. Radiotherapy (RT) is the most effective non-surgical treatment modality used in GBM and is a crucial component of standard of care for the majority of patients. RT is an effective treatment but causes irreversible cognitive impairments that worsen over time. Understanding the mechanisms underlying RT induced cognitive impairment will allow us to directly target this clinical unmet need in patients. Higher order brain functions such as cognition rely on the integrity of local and global neural synchrony and are mediated by GABAergic networks. GABAergic interneurons are strongly implicated in pathological states associated with cognitive dysfunction, with deficits in the parvalbumin interneuron (PVI) subset correlating with cognitive decline across multiple disease models. Our previous investigations (including both clinical and preclinical studies) have implicated these PVIs in the cognitive deficits associated with both schizophrenia and Alzheimer's disease. In the current project, we plan to undertake longitudinal behavioural, electrophysiological and quantitative post-mortem (immunohistochemical and automated western detection) studies to investigate mechanisms underlying cognitive deficits following RT treatment. A further aim of the project will be to evaluate the impact of rationale pharmacological interventions (targeting neuroinflammatory and GABAergic systems) to prevent/reverse the neurotoxic effects of brain RT

胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，也是一种需求极度未得到满足的癌症。虽然临床结果仍然不佳，但总体生存率在过去 20 年中有所上升，揭示了治疗相关神经系统并发症的破坏性影响。放射治疗 (RT) 是 GBM 最有效的非手术治疗方式，也是大多数患者护理标准的重要组成部分。放疗是一种有效的治疗方法，但会导致不可逆的认知障碍，并随着时间的推移而恶化。了解放疗引起的认知障碍的机制将使我们能够直接针对患者这一临床未满足的需求。认知等高级大脑功能依赖于局部和全局神经同步的完整性，并由 GABA 能网络介导。 GABA能中间神经元与认知功能障碍相关的病理状态密切相关，小清蛋白中间神经元（PVI）子集的缺陷与多种疾病模型中的认知能力下降相关。我们之前的研究（包括临床和临床前研究）表明这些 PVI 与精神分裂症和阿尔茨海默病相关的认知缺陷有关。在当前的项目中，我们计划进行纵向行为、电生理学和定量尸检（免疫组织化学和自动蛋白质检测）研究，以调查 RT 治疗后认知缺陷的机制。该项目的另一个目标是评估合理的药理学干预措施（针对神经炎症和 GABA 系统）的影响，以预防/逆转脑 RT 的神经毒性作用