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：
10267303
负责人：
Munjal M Acharya
金额：
$ 42万
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/10267303
关键词：
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 5a Complement Activation Complex Cranial Irradiation Data Set 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 of activation protein Medical Metastatic malignant neoplasm to brain Microglia Molecular Mus Nerve Degeneration Neurobiology Oral Outcome Study Oxidative Stress Patients Pharmacology 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 Time Tissues Transgenic Organisms astrogliosis base blood-brain barrier permeabilization cancer invasiveness cancer therapy clinically relevant cognitive development cognitive function complement 1q receptor complement system cytokine design effectiveness testing glial activation improved knock-down link protein mouse model neurogenesis neuroinflammation neurotransmission novel 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：辐射引起的脑损伤中的胶质免疫信号传导。用于治疗中枢神经系统癌症的颅放射疗法（CRT）通常会导致意外和认知障碍使人衰弱。 CRT也仍然是对抗大脑的护理标准其他侵入性癌症的转移。但是，分子和细胞机制基本的CRT引起的认知下降是多方面的，尚未完全解决。我们过去的发现表明，全脑，急性CRT会引起进步神经退行性的变化，包括氧化应激，神经发生减少和增加神经炎症。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保持数千个积极参与认知的突触。但是，我们有表明CRT诱导的认知破坏与星形细胞肥大一致，升高啮齿动物模型中星形胶质细胞基因的表达和持续的小胶质细胞活化。所以，我们假设有害的神经胶质信号显着导致认知缺陷。补体系统是神经胶质激活的潜在介体，但也有一系列非 - 中枢神经系统中的免疫功能，包括凋亡细胞的突触修剪和清除率细胞碎片，如果失调，这是有害的。特别是表达式的全球高度在神经退行性条件下，CNS中的C1Q和C3完成。我们的发现表明急性，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，补体蛋白的共表达（C1Q，C3）和特定受体的升高（C5AR1，TLR4）与认知障碍相吻合。反应性神经胶质病已被证明上调完成的级联蛋白质，这些蛋白具有破坏性的突触并与之相关的神经变性。我们假设脑癌治疗引起的异常激活神经胶质补体级联导致认知缺陷。我们的假设得到了两个关键的支持针对上游（C1Q）和下游的目标完成信号的初步数据集（C5A）激活分支点。首先，有条件的小胶质细胞选择性C1Q（敲低）暴露到CRT的小鼠没有暴露于认知受损，并且表现出缺乏神经炎症为与受辐照的WT小鼠相比。其次，用口服活性的BBB渗透的C5A处理受体（C5AR1）拮抗剂改善了急性CRT诱导的认知缺陷，并缓解了辐照大脑中的小胶质细胞激活。我们的假设将使用临床上解决相关，分级，局灶性颅辐射范式±替诺唑胺，转基因和神经胶质瘤 - 轴承合成小鼠模型和旨在测试机制的药物方法和治疗性干预措施以恢复受损动物的认知功能。