Therapeutic Irradiation and Brain Functions

治疗辐射和脑功能

基本信息

批准号：
10053714
负责人：
NALIN GUPTA
金额：
$ 35.16万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-09 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053714
关键词：
Affect Animals Astrocytes Behavioral Brain Brain Neoplasms CCL2 gene Cellular Structures Chronic Clinical 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 Infrastructure 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 Neurons Oxidative Stress Pathogenicity Peripheral Pharmacology Phase Phase I Clinical Trials Phase II Clinical Trials Phenotype Play Population Predisposition Process Quantitative Reverse Transcriptase PCR Radiation Radiation Dose Unit Radiation Injuries Reporter Research Role Signal Transduction Structure Synapses Synaptic Transmission Temporal Lobe Testing Therapeutic Time Work biological adaptation to stress central nervous system injury chemokine receptor clinically relevant cognitive change cognitive function combinatorial information processing innovation irradiation macrophage monocyte mouse model neuroinflammation new therapeutic target novel prevent radiation-induced cognitive dysfunction recruit relating to nervous system response synaptic function treatment strategy

项目摘要

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.

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。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The dark side of antiviral T cell responses.

抗病毒 T 细胞反应的阴暗面。

DOI：
10.1038/s41593-019-0454-8
发表时间：
2019
期刊：
Nature neuroscience
影响因子：
25
作者：
Krukowski,Karen;Rosi,Susanna
通讯作者：
Rosi,Susanna

Roadmap for Advancing Pre-Clinical Science in Traumatic Brain Injury.

DOI：
10.1089/neu.2021.0094
发表时间：
2021-12
期刊：
Journal of neurotrauma
影响因子：
4.2
作者：
Smith DH;Kochanek PM;Rosi S;Meyer R;Ferland-Beckham C;Prager EM;Ahlers ST;Crawford F
通讯作者：
Crawford F

Rescue of cognitive function following fractionated brain irradiation in a novel preclinical glioma model.

DOI：
10.7554/elife.38865
发表时间：
2018-11-13
期刊：
eLife
影响因子：
7.7
作者：
Feng X;Liu S;Chen D;Rosi S;Gupta N
通讯作者：
Gupta N

Microglia: Ally and Enemy in Deep Space.

小胶质细胞：深空中的盟友和敌人。

DOI：
10.1016/j.neubiorev.2021.03.036
发表时间：
2021
期刊：
Neuroscience and biobehavioral reviews
影响因子：
8.2
作者：
Rienecker,KiraDA;Paladini,MariaSerena;Grue,Katherine;Krukowski,Karen;Rosi,Susanna
通讯作者：
Rosi,Susanna

Central Nervous System Responses to Simulated Galactic Cosmic Rays.