Therapeutic Irradiation and Brain Functions
Therapeutic Irradiation and Brain Functions
批准号:
9242504
负责人:
Susanna Rosi
金额:
$38.23万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-12-09 至 2021-11-30
关键词:
AffectAnimalsAstrocytesBehavioralBrainBrain NeoplasmsCCL2 geneCellular StructuresChronicClinicalClinical TrialsCognitionCognitive deficitsCranial IrradiationDataDiscriminationDoseEnvironmentEvolutionFlow CytometryFunctional disorderFundingGenesGeneticGenetic ModelsGenetic TranscriptionGenotypeGoalsHippocampus (Brain)ImmuneImmunohistochemistryImpaired cognitionInfiltrationInflammationInflammatoryInflammatory ResponseInnate Immune SystemIonizing radiationKineticsLate EffectsLearningLightLinkMacrophage Colony-Stimulating Factor ReceptorMeasuresMediatingMemoryMemory impairmentMethodsMicrogliaMolecularMultivariate AnalysisMusMyeloid CellsNerve DegenerationNervous System PhysiologyNeuraxisNeuronsOxidative StressPathogenicityPeripheralPharmacologyPhasePhenotypePlayPopulationPredispositionProcessQuantitative Reverse Transcriptase PCRRadiationRadiation InjuriesRecruitment ActivityReporterResearchResearch InfrastructureRoleSignal TransductionStructureSynapsesSynaptic TransmissionTemporal LobeTestingTherapeuticTimeWorkbiological adaptation to stresschemokine receptorclinically relevantcognitive changecognitive functioncombinatorialinformation processinginjuredinnovationirradiationmacrophagemonocytemouse modelneuroinflammationnew therapeutic targetnovelpermissivenesspreventradiation-induced cognitive dysfunctionrelating to nervous systemresponsesynaptic functiontreatment strategy
中文摘要
项目摘要
放射治疗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一系列晚期效应目前没有治疗方法
甚至可以部分逆转辐射损伤后观察到的认知变化。特别是,辐射的
颞叶可以深刻地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,
多个神经过程和突触传递最终导致海马功能的破坏。
值得注意的是,常驻小胶质细胞和浸润单核细胞,神经炎症过程中的关键细胞,
有不同的胚胎起源,也有不同的功能。激活的机制
炎症反应对脑照射后认知功能的影响及不同的特异性作用
骨髓细胞仍然难以捉摸。因此,有明确的需要了解辐射损伤的机制,
炎症,以制定预防颅脑照射后认知能力下降的策略。
我们小组最近在上一个资助期的工作揭示了这些问题,
揭示了辐射诱导记忆的细胞和分子机制中的具体问题
赤字具体来说,我们的数据表明了CCL 2/CCR 2与认知之间的直接联系。这些结果
提供了脑照射后外周先天免疫系统与认知之间的机制联系。在
目前的建议,我们将评估中心假设,治疗剂量的颅照射诱导
外周单核细胞浸润,改变固有的炎症反应并促进突触
功能障碍和长期认知缺陷。
目的1:确定放射诱导的骨髓细胞改变的动力学和炎症表型
在单次和低分次治疗剂量的照射后。
目的2:评价外周血单核细胞募集到脑中作为脑缺血再灌注机制驱动因素的作用。
辐射引起的突触和认知功能的改变。
目的3:确定髓样细胞的暂时性耗竭是否可以防止突触功能和认知的丧失
在单次和大剂量放射后。
关于辐射诱导的病理生理学的演变,
外周来源的巨噬细胞积聚或炎症,以及这与突触和
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。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Aging exacerbates trauma-induced immune pathways and neuronal dysfunction
-
批准号:10159815
-
项目类别:
-
资助金额:$33.93万
-
财政年份:2017
-
负责人:Susanna Rosi
-
依托单位:
Aging exacerbates trauma-induced immune pathways and neuronal dysfunction
-
批准号:9924452
-
项目类别:
-
资助金额:$35.23万
-
财政年份:2017
-
负责人:Susanna Rosi
-
依托单位:
Contribution of infiltrating macrophages on synaptic function after TBI
-
批准号:8828464
-
项目类别:
-
资助金额:$23.71万
-
财政年份:2014
-
负责人:Susanna Rosi
-
依托单位:
Effects of traumatic brain injury on hippocampal network activity: age difference
-
批准号:8443632
-
项目类别:
-
资助金额:$23.54万
-
财政年份:2013
-
负责人:Susanna Rosi
-
依托单位:
Effects of traumatic brain injury on hippocampal network activity: age difference
-
批准号:8669899
-
项目类别:
-
资助金额:$19.74万
-
财政年份:2013
-
负责人:Susanna Rosi
-
依托单位:
Brain Irradiation Affects Neuronal Function
-
批准号:8256616
-
项目类别:
-
资助金额:$31.1万
-
财政年份:2009
-
负责人:Susanna Rosi
-
依托单位:
Brain Irradiation Affects Neuronal Function
-
批准号:7846906
-
项目类别:
-
资助金额:$32.06万
-
财政年份:2009
-
负责人:Susanna Rosi
-
依托单位:
Brain Irradiation Affects Neuronal Function
-
批准号:8461061
-
项目类别:
-
资助金额:$29.23万
-
财政年份:2009
-
负责人:Susanna Rosi
-
依托单位:
Brain Irradiation Affects Neuronal Function
-
批准号:8067979
-
项目类别:
-
资助金额:$31.1万
-
财政年份:2009
-
负责人:Susanna Rosi
-
依托单位:
Brain Irradiation Affects Neuronal Function
-
批准号:7731544
-
项目类别:
-
资助金额:$30.7万
-
财政年份:2009
-
负责人:Susanna Rosi
-
依托单位:
海外基金