Myeloid cells and radiation-induced memory deficits in rodent glioma model: sex and age effects
Myeloid cells and radiation-induced memory deficits in rodent glioma model: sex and age effects
批准号:
10425330
负责人:
NALIN GUPTA
金额:
$36.69万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-07-01 至 2025-06-30
关键词:
AddressAdolescentAffectAgeAnimal ModelAnimalsBiologicalBiological AssayBrainBrain NeoplasmsCellular AssayCellular StructuresCentral Nervous System NeoplasmsChromatinClinicalCognitive deficitsCranial IrradiationDataDendritic SpinesDevelopmentEuchromatinEvolutionFemaleFunctional disorderGenderGene ExpressionGliomaGoalsHippocampus (Brain)ImmuneImmune systemImmunocompetentImpaired cognitionIndividualInflammationInflammatory ResponseInnate Immune SystemIonizing radiationIonsLate EffectsLearningLinkMeasuresMediatingMemoryMemory impairmentMicrogliaModelingModificationMusMyeloid CellsNatureNeuraxisNeurobiologyNeuronsPatientsPeripheralPhenotypePre-Clinical ModelPredispositionProcessProto-Oncogene Protein c-kitPublishingRadiationRadiation InjuriesRodentRoleSignal TransductionSynapsesSynaptic TransmissionSynaptosomesTemporal LobeTherapeuticTimeTransposaseTyrosine Kinase Inhibitorage effectbrain irradiation injuryclinically relevantcognitive changecognitive functionconventional therapyexperimental studygenome-widein vivoinhibitorirradiationmacrophagemalemodel designmonocyteneuroinflammationphenotypic biomarkerpre-clinicalpreventradiation during childhoodradiation-induced cognitive dysfunctionrecruitrelating to nervous systemsexsingle-cell RNA sequencingsynaptic functiontranscriptometranscriptomicstumoryoung adult
中文摘要
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,
包括进行性认知功能障碍在内的许多迟发效应。这些认知上的变化,
在儿童时期接受过放射治疗的人中严重。结果的程度和性质
认知缺陷可能受年龄、治疗和性别的影响。这种差异的神经生物学原因
是未知的,很少有实验研究已经解决了这个问题。啮齿类动物的电离辐射
一致显示激活几个神经炎症信号级联,可以影响多个神经元
过程和突触传递,最终破坏海马功能。神经炎症,
特征在于脑内驻留的小胶质细胞的活化和外周来源的单核细胞的募集
(统称为“骨髓细胞”),一直与认知功能的丧失有关,
辐射后的老鼠仍然没有预防或治疗辐射引起的认知功能障碍的方法。
功能障碍尽管有大量的临床证据表明分次脑照射与认知缺陷有关,
在这一观察的生物学基础上仍然存在着未解的缺口:
炎症反应影响认知功能,且有年龄和性别的影响。此外,没有
概括最常见临床情况特征的临床前模型:
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,组成和
脑辐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。本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
在设计用于模拟临床环境中使用的常规治疗范例的脑肿瘤模型中。具体
支持我们假设的目标是:
1.建立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.评价骨髓细胞作为fWBI后永久性记忆缺陷的机制驱动因素的作用。
在外周血中,关于辐射诱导的病理生理学的演变知之甚少。
衍生的巨噬细胞积聚或炎症,以及这与突触和认知功能改变的关系
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。
英文摘要
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.
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会议论文
Myeloid cells and radiation-induced memory deficits in rodent glioma model: sex and age effects
-
批准号:10180919
-
项目类别:
-
资助金额:$37.41万
-
财政年份:2020
-
负责人:NALIN GUPTA
-
依托单位:
Myeloid cells and radiation-induced memory deficits in rodent glioma model: sex and age effects
-
批准号:10668445
-
项目类别:
-
资助金额:$36.69万
-
财政年份:2020
-
负责人:NALIN GUPTA
-
依托单位:
Therapeutic Irradiation and Brain Functions
-
批准号:10053714
-
项目类别:
-
资助金额:$35.16万
-
财政年份:2016
-
负责人:NALIN GUPTA
-
依托单位:
Macrophage and Microglial Activation in Glioma-Associated Inflammation
-
批准号:7389647
-
项目类别:
-
资助金额:$16.14万
-
财政年份:2006
-
负责人:NALIN GUPTA
-
依托单位:
Macrophage and Microglial Activation in Glioma-Associated Inflammation
-
批准号:7225185
-
项目类别:
-
资助金额:$16.14万
-
财政年份:2006
-
负责人:NALIN GUPTA
-
依托单位:
Macrophage and Microglial Activation in Glioma-Associated Inflammation
-
批准号:7582246
-
项目类别:
-
资助金额:$16.14万
-
财政年份:2006
-
负责人:NALIN GUPTA
-
依托单位:
Macrophage and Microglial Activation in Glioma-Associated Inflammation
-
批准号:7087265
-
项目类别:
-
资助金额:$16.14万
-
财政年份:2006
-
负责人:NALIN GUPTA
-
依托单位:
Macrophage and Microglial Activation in Glioma-Associated Inflammation
-
批准号:7776858
-
项目类别:
-
资助金额:$16.14万
-
财政年份:2006
-
负责人:NALIN GUPTA
-
依托单位:
海外基金