Myeloid cells and radiation-induced memory deficits in rodent glioma model: sex and age effects

啮齿动物神经胶质瘤模型中的骨髓细胞和辐射引起的记忆缺陷：性别和年龄的影响

• 批准号: 10180919
• 负责人: NALIN GUPTA
• 金额: $ 37.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10180919
• 关键词: Address; Adolescent; Affect; Age; Animal Model; Animals; Biological; Biological Assay; Brain; Brain Neoplasms; Cellular Assay; Cellular Structures; Central Nervous System Neoplasms; Childhood; Chromatin; Clinical; Cognitive deficits; Cranial Irradiation; Data; Dendritic Spines; Development; Euchromatin; Evolution; Female; Functional disorder; Gender; Gene Expression; Glioma; Goals; Hippocampus (Brain); Immune; Immune system; Immunocompetent; Impaired cognition; Individual; Inflammation; Inflammatory Response; Innate Immune System; Ionizing radiation; Ions; Late Effects; Learning; Link; Measures; Mediating; Memory; Memory impairment; Microglia; Modeling; Modification; Mus; Myeloid Cells; Nature; Neuraxis; Neurobiology; Neurons; Patients; Peripheral; Phenotype; Pre-Clinical Model; Predisposition; Process; Proto-Oncogene Protein c-kit; Publishing; Radiation; Radiation Injuries; Rodent; Role; Signal Transduction; Synapses; Synaptic Transmission; Synaptosomes; Temporal Lobe; Therapeutic; Time; Transposase; Tyrosine Kinase Inhibitor; age effect; brain irradiation injury; clinically relevant; cognitive change; cognitive function; conventional therapy; experimental study; genome-wide; in vivo; inhibitor/antagonist; irradiation; macrophage; male; model design; monocyte; neuroinflammation; phenotypic biomarker; pre-clinical; prevent; radiation-induced cognitive dysfunction; recruit; relating to nervous system; sex; single-cell RNA sequencing; synaptic function; transcriptome; transcriptomics; tumor; young adult

Project Summary/Abstract Ionizing irradiation is commonly used to treat both primary and metastatic brain tumors and can cause a number of late effects including progressive cognitive dysfunction. These cognitive changes are particularly severe in individuals who were treated with radiation during childhood. The extent and nature of the resulting cognitive deficits may be influenced by age, treatment and gender . The neurobiological reason for this difference is unknown, and very few experimental studies have addressed this issue. Ionizing radiation in rodents has been consistently shown to activate several neuroinflammatory signaling cascades that can impact multiple neural processes and synaptic transmission, ultimately disrupting hippocampal function. Neuroinflammation, characterized by activation of brain resident microglia and recruitment of peripherally derived monocytes (collectively referred to as `myeloid cells'), has been consistently associated with the loss of cognitive function in mice after radiation. There are still no treatments for preventing or treating radiation-induced cognitive dysfunction. Despite the extensive clinical evidence linking fractionated brain irradiation with cognitive deficits, there are still unanswered gaps in the biologic basis of this observation: the mechanism/s by which activation of the inflammatory response affect cognitive function, and the effect of age and sex. Furthermore, there are no pre-clinical models that recapitulate the features of the most common clinical scenario: patients with central nervous system (CNS) tumors. Our final therapeutic goal is to prevent and treat the cognitive changes observed after fractionated whole-brain irradiation (fWBI) injury. We hypothesize that changes in the composition and function of myeloid cells following brain irradiation can both prevent and rescue cognitive deficits through durable effects on synapses. The translational objective of this proposal is to demonstrate that resetting the immune system by brief microglia depletion prevents the long-term development of memory deficits in a brain tumor model designed to mimic conventional treatment paradigms used in clinical settings. The specific aims in support of our hypothesis are: 1. Establish the effects of fWBI on memory and synaptic composition as a function of age and sex in an immunocompetent mouse glioma model. 2. Determine the role of myeloid cells in the development of fWBI-induced memory deficits. 3. Evaluate the role of myeloid cells as a mechanistic driver of the permanent memory deficits after fWBI. Very little is known in regard to the evolution of radiation induced pathophysiology in the context of peripherally derived macrophage accumulation or inflammation, and how this relates to altered synaptic and cognitive function. Our final therapeutic goal is to modify the cognitive changes observed after radiation injury.

项目概要/摘要 电离辐射通常用于治疗原发性和转移性脑肿瘤，并可引起 许多后期影响，包括进行性认知功能障碍。这些认知变化尤其 对于童年时期接受过放射治疗的个体来说，情况更为严重。结果的范围和性质 认知缺陷可能受到年龄、治疗和性别的影响。这种差异的神经生物学原因 未知，并且很少有实验研究解决这个问题。啮齿动物中的电离辐射 一致显示可激活多种神经炎症信号级联，从而影响多种神经 过程和突触传递，最终破坏海马功能。神经炎症， 其特征是激活大脑驻留小胶质细胞和招募外周来源的单核细胞 （统称为“骨髓细胞”）一直与认知功能丧失相关 辐射后的小鼠。仍然没有预防或治疗辐射引起的认知障碍的治疗方法 功能障碍。尽管有大量临床证据表明分次脑部照射与认知缺陷有关， 这一观察结果的生物学基础仍然存在未解答的空白：激活的机制 炎症反应影响认知功能，并受年龄和性别的影响。此外，没有 临床前模型概括了最常见临床情况的特征：患有中枢神经系统疾病的患者 神经系统（CNS）肿瘤。我们的最终治疗目标是预防和治疗观察到的认知变化 分次全脑照射（fWBI）损伤后。我们假设成分发生变化 脑部照射后骨髓细胞的功能可以预防和挽救认知缺陷 通过对突触的持久影响。该提案的翻译目标是证明 通过短暂的小胶质细胞耗竭来重置免疫系统可以防止记忆缺陷的长期发展 在旨在模仿临床环境中使用的常规治疗范例的脑肿瘤模型中。具体的 支持我们假设的目标是： 1. 确定 fWBI 对记忆和突触组成的影响，作为年龄和性别的函数 免疫活性小鼠神经胶质瘤模型。 2. 确定骨髓细胞在 fWBI 诱导的记忆缺陷发展中的作用。 3. 评估骨髓细胞作为 fWBI 后永久性记忆缺陷的机械驱动因素的作用。 关于外周辐射诱发的病理生理学的演变，人们知之甚少。 衍生的巨噬细胞积聚或炎症，以及这与突触和认知改变的关系 功能。我们的最终治疗目标是改变放射损伤后观察到的认知变化。