Glial immune signaling in radiation-induced brain injury

放射诱发的脑损伤中的胶质细胞免疫信号传导

基本信息

批准号：
10693817
负责人：
Munjal M Acharya
金额：
$ 43.02万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693817
关键词：
Ablation Acute Address Adult Aftercare Alzheimer&apos s Disease Anaphylatoxins Animals Apoptotic Astrocytes Behavior assessment Biopsy Brain Brain Injuries Brain Neoplasms C5a anaphylatoxin receptor Cancer Survivor Cells Childhood Chronic Clinical Clinical Management Cognition Cognitive Cognitive deficits Complement Complement 1q Complement 3a Complement 5a Complement Activation Complex Cranial Irradiation Data Set Development Dose Epilepsy Foundations Gene Expression Genes Genetic Glioma Gliosis Hour Human Hypertrophy Immune signaling Immunocompetent Impaired cognition Impairment Inflammation Intervention Link Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of central nervous system Mediating Mediator Medical Metastatic malignant neoplasm to brain Microglia Molecular Mus Nerve Degeneration Neurobiology Oral Outcome Study Oxidative Stress Patients Play Production Prognosis Proteins Quality of life Radiation Radiation therapy Receptor Inhibition Reporting Rodent Model Role Signal Transduction Synapses TLR4 gene Testing Therapeutic Therapeutic Intervention Tissues Transgenic Organisms antagonist astrogliosis blood-brain barrier permeabilization brain dysfunction cancer invasiveness cancer therapy clinically relevant cognitive function complement 1q receptor complement system cytokine design effectiveness testing glial activation improved knock-down link protein mouse model neurogenesis neuroinflammation neuroprotection neurotransmission novel pharmacologic receptor response restoration standard of care stem cell proliferation synaptic pruning temozolomide therapy design treatment response tumor tumorigenic

项目摘要

ABSTRACT: Glial immune signaling in radiation-induced brain injury. Cranial radiation therapy (CRT) for the treatment of CNS cancers often leads to unintended and debilitating cognitive impairments. CRT also remains the standard of care to counter brain metastases for other invasive cancers. However, the molecular and cellular mechanisms underlying CRT-induced cognitive decline are multifaceted and have not been completely resolved. Our past findings show that whole-brain, acute CRT induces progressive neurodegenerative changes, including oxidative stress, reduced neurogenesis, and increased neuroinflammation. Microglia and astrocytes form complex glial networks in the CNS by pruning and maintaining thousands of synapses that are actively involved in cognition. Yet, we have shown that CRT-induced cognitive disruption coincides with astrocytic hypertrophy, elevated expression of astrogliosis genes, and persistent microglial activation in rodent models. Therefore, we hypothesize that detrimental glial signaling significantly contributes to cognitive deficits. The complement system is a potent mediator of the glial activation, but it also has a range of non- immune functions in the CNS, including synaptic pruning and clearance of apoptotic cells and cellular debris which is detrimental if dysregulated. Particularly, global elevation in the expression of complement C1q and C3 in the CNS has been reported in neurodegenerative conditions. Our findings indicate that acute, whole-brain CRT-mediated chronic microglial activation and reactive astrocytes, elevated co-expression of complement proteins (C1q, C3) and specific receptors (C5aR1, TLR4) coincided with cognitive impairments. Reactive gliosis has been shown to upregulate complement cascade proteins that are destructive to synapses and associated with neurodegeneration. We hypothesize that brain cancer therapy-induced aberrant activation in the glial complement cascade leads to cognitive deficits. Our hypothesis is supported by two key preliminary data sets targeting complement signaling at the upstream (C1q) and the downstream (C5a) activation branch points. First, exposure of conditional microglia-selective C1q (knockdown) mice to CRT did not exhibit impaired cognition and showed a lack of neuroinflammation as compared to irradiated WT mice. Second, treatment with an orally active, BBB permeable, C5a receptor (C5aR1) antagonist ameliorated acute CRT-induced cognitive deficits and alleviated microglial activation in the irradiated brain. Our hypothesis will be addressed using a clinically relevant, fractionated, focal cranial irradiation paradigm ± temozolomide, transgenic and glioma- bearing syngeneic mouse models, and pharmacologic approaches designed to test mechanisms and therapeutic interventions to restore cognitive function in the impaired animals.

摘要：放射诱发的脑损伤中的神经胶质免疫信号传导。用于治疗中枢神经系统癌症的颅脑放射治疗 (CRT) 常常会导致意想不到的副作用 CRT 仍然是对抗脑损伤的标准治疗方法。然而，其他侵袭性癌症的转移的分子和细胞机制。 CRT 引起的认知能力下降是多方面的，并且尚未完全得到解决我们过去的研究结果表明，全脑急性 CRT 会导致进展。神经退行性变化，包括氧化应激、神经发生减少和神经发生增加小胶质细胞和星形胶质细胞通过修剪在中枢神经系统中形成复杂的神经胶质网络。并维持数千个积极参与认知的突触。研究表明，CRT 引起的认知障碍与星形胶质细胞肥大同时发生，因此，星形胶质细胞增生基因的表达以及啮齿动物模型中小胶质细胞的持续激活。我们发现神经胶质信号显着导致认知缺陷。补体系统是神经胶质细胞激活的有效介质，但它也具有一系列非- 中枢神经系统的免疫功能，包括突触修剪和凋亡细胞的清除细胞碎片如果失调的话会带来痛苦，特别是表达的整体升高。我们已经报道了神经退行性疾病中 CNS 中补体 C1q 和 C3 的减少。研究结果表明，急性、全脑 CRT 介导的慢性小胶质细胞激活和反应性星形胶质细胞，补体蛋白（C1q、C3）和特定受体的共表达升高（C5aR1、TLR4）与认知障碍同时发生。上调对突触具有破坏性并与相关的补体级联蛋白我们采取了脑癌治疗引起的异常激活。神经胶质补体级联会导致认知缺陷，我们的假设得到两个关键的支持。针对上游 (C1q) 和下游补体信号传导的初步数据集 (C5a) 激活分支点首先，暴露条件性小胶质细胞选择性 C1q（敲低）。接受 CRT 治疗的小鼠没有表现出认知受损，并且没有表现出神经炎症其次，使用口服活性、BBB 可渗透的 C5a 进行治疗。受体（C5aR1）拮抗剂可改善急性 CRT 诱导的认知缺陷并缓解我们的假设将通过临床来解决。相关的、分次的、局灶性颅脑照射范式±替莫唑胺、转基因和神经胶质瘤- 具有同基因小鼠模型和旨在测试机制的药理学方法以及恢复受损动物认知功能的治疗干预。