Therapeutic Irradiation and Brain Functions

治疗辐射和脑功能

• 批准号: 9242504
• 负责人: Susanna Rosi
• 金额: $ 38.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-09 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242504
• 关键词: Affect; Animals; Astrocytes; Behavioral; Brain; Brain Neoplasms; CCL2 gene; Cellular Structures; Chronic; Clinical; Clinical Trials; Cognition; Cognitive deficits; Cranial Irradiation; Data; Discrimination; Dose; Environment; Evolution; Flow Cytometry; Functional disorder; Funding; Genes; Genetic; Genetic Models; Genetic Transcription; Genotype; Goals; Hippocampus (Brain); Immune; Immunohistochemistry; Impaired cognition; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Ionizing radiation; Kinetics; Late Effects; Learning; Light; Link; Macrophage Colony-Stimulating Factor Receptor; Measures; Mediating; Memory; Memory impairment; Methods; Microglia; Molecular; Multivariate Analysis; Mus; Myeloid Cells; Nerve Degeneration; Nervous System Physiology; Neuraxis; Neurons; Oxidative Stress; Pathogenicity; Peripheral; Pharmacology; Phase; Phenotype; Play; Population; Predisposition; Process; Quantitative Reverse Transcriptase PCR; Radiation; Radiation Injuries; Recruitment Activity; Reporter; Research; Research Infrastructure; Role; Signal Transduction; Structure; Synapses; Synaptic Transmission; Temporal Lobe; Testing; Therapeutic; Time; Work; biological adaptation to stress; chemokine receptor; clinically relevant; cognitive change; cognitive function; combinatorial; information processing; injured; innovation; irradiation; macrophage; monocyte; mouse model; neuroinflammation; new therapeutic target; novel; permissiveness; prevent; radiation-induced cognitive dysfunction; relating to nervous system; response; synaptic function; treatment strategy

Project Summary Therapeutic irradiation is commonly used to treat both primary and metastatic brain tumors and can cause a number of late effects including progressive cognitive dysfunction. There is no treatment currently available that can even partially reverse cognitive changes observed after radiation injury. Specifically, irradiation of the temporal lobe can profoundly affect the cellular structures mediating learning and memory. Ionizing radiation has also been consistently shown to activate several neuroinflammatory signaling cascades that can impact multiple neural processes and synaptic transmission ultimately causing disruptions in hippocampal function. Notably, resident microglia and infiltrating monocytes, the key cellular player in neuroinflammatory processes, have distinct embryological origins and also fulfill different functions. The mechanism/s by which activation of the inflammatory response affect cognitive functions after brain irradiation and the specific role of different myeloid cells remain elusive. Thus, there is a clear need to understand the mechanisms of radiation injury and inflammation to develop strategies for preventing cognitive decline following cranial irradiation. Recent work from our group during the previous funding period has shed light in these questions and revealed specific problems in the cellular and molecular mechanisms underlying radiation-induced memory deficits. Specifically our data demonstrates a direct link between CCL2/CCR2 and cognition. These results provide a mechanistic link between peripheral innate immune system and cognition after brain irradiation. In the current proposal we will evaluate the central hypothesis that therapeutic doses of cranial irradiation induce infiltration of peripheral monocytes that modifies the resident inflammatory response and promotes synaptic dysfunction and long term cognitive deficits. Aim 1: Determine the kinetics and inflammatory phenotype of radiation-induced myeloid cell alterations after single and hypofractionated therapeutic doses of irradiation. Aim 2: Evaluate the role of peripheral monocyte recruitment into the brain as a mechanistic driver of radiation-induced altered synaptic and cognitive functions. Aim 3: Determine if temporary depletion of myeloid cells prevent the loss of synaptic function and cognition after single and hypofractionated doses of radiation. 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 治疗性放射通常用于治疗原发性和转移性脑肿瘤，并可能导致 许多后期影响，包括进行性认知功能障碍。目前没有可用的治疗方法 甚至可以部分逆转辐射损伤后观察到的认知变化。具体而言，照射 颞叶可以深刻影响介导学习和记忆的细胞结构。电离辐射 也一直被证明可以激活几种神经炎症信号级联反应，从而影响 多种神经过程和突触传递最终导致海马功能中断。 值得注意的是，常驻小胶质细胞和浸润单核细胞是神经炎症过程中的关键细胞参与者， 具有不同的胚胎起源并履行不同的功能。激活的机制 脑照射后炎症反应影响认知功能及不同药物的具体作用 骨髓细胞仍然难以捉摸。因此，明确需要了解辐射损伤的机制和 炎症以制定预防颅脑照射后认知能力下降的策略。 我们小组在上一个资助期间的最新工作揭示了这些问题和 揭示了辐射诱发记忆的细胞和分子机制中的具体问题 赤字。具体来说，我们的数据证明了 CCL2/CCR2 与认知之间的直接联系。这些结果 提供外周先天免疫系统与脑照射后认知之间的机制联系。在 目前的提议，我们将评估治疗剂量的颅脑照射诱发的中心假设 外周单核细胞浸润，改变常驻炎症反应并促进突触 功能障碍和长期认知缺陷。 目标 1：确定辐射诱导的骨髓细胞改变的动力学和炎症表型 单次和大分割治疗剂量的照射后。 目标 2：评估外周单核细胞募集至大脑作为机械驱动因素的作用 辐射引起的突触和认知功能改变。 目标 3：确定骨髓细胞的暂时耗竭是否可以防止突触功能和认知的丧失 单次和大分割剂量的放射治疗后。 关于辐射诱发的病理生理学的演变知之甚少。 外周源性巨噬细胞积聚或炎症，以及这与突触和炎症改变的关系 认知功能。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。