Immune Contribution to Brain Atrophy

免疫对脑萎缩的影响

• 批准号: 9272449
• 负责人: Aaron J Johnson
• 金额: $ 19.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9272449
• 关键词: Acute; Address; Alzheimer' s Disease; Animals; Atrophic; Biological Models; CD8-Positive T-Lymphocytes; Cells; Cerebral Palsy; Cognitive; Cognitive deficits; Confocal Microscopy; Cre-LoxP; Data; Dementia; Demyelinating Diseases; Demyelinations; Development; Encephalitis; Epilepsy; Etiology; FVB Mouse; Flow Cytometry; Future; Globoid cell leukodystrophy; Huntington Disease; Immune; Immunohistochemistry; Immunologics; Impairment; Infection; Inflammation; Inflammatory; Laboratories; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mammals; Mediating; Methodology; Modeling; Molecular; Mouse Strains; Multiple Sclerosis; Nerve Degeneration; Neuraxis; Neurologic; Neurons; Neurosyphilis; Pick Disease of the Brain; Picornaviridae Infections; Primary Progressive Multiple Sclerosis; Publishing; Reagent; Research; Resolution; Role; Solid; System; Systems Development; TMEV; Testing; Therapeutic Intervention; Time; Transgenes; Transgenic Mice; Transgenic Organisms; Virus; base; behavioral study; cell type; cerebral atrophy; design; early onset; endoplasmic reticulum stress; in vivo; innovation; model development; motor deficit; mouse model; nervous system disorder; neuroAIDS; neuroinflammation; novel; response

ABSTRACT Brain atrophy, otherwise classified as CNS neurodegeneration (CNS-ND), is a common feature of neurological diseases as diverse as Alzheimer's disease, cerebral palsy, dementia, Pick’s disease, Huntington's disease, Krabbe disease, multiple sclerosis (MS), Epilepsy, Encephalitis, Neurosyphilis, and neuroAIDS. How brain atrophy occurs in neurological diseases remains to be fully defined. However, neuronal impairment, infection, and neuroinflammation have been put forward as putative mechanisms of CNS-ND. CNS-ND overall remains irreversible and has correlated with cognitive and motor deficits. Furthermore, the observation of brain atrophy being a feature of so many pressing neurological conditions necessitates the development of model systems to determine the cellular and molecular basis for CNS-ND. Our research team recently published the first study of CNS-ND using the Theiler’s virus model of primary progressive MS. In this proposal, we introduce a novel model of acute brain atrophy that presents in the FVB mouse strain. The discovery of CNS-ND in TMEV infected FVB mice enables the use of powerful transgenic approaches to define the etiology of brain atrophy. Transgenic FVB mice that express the H-2Db (Db) class I molecule gain a new CD8 T cell response during TMEV infection and have early onset brain atrophy. We propose to test our central hypothesis that neuroinflammation contributes to CNS-ND. Based on solid preliminary data, and through the use of our unique methodology, models, and reagents, we plan to pursue the following two aims: Specific Aim #1 – Determine the extent CNS-ND is mediated through CD8 T cell responses. Specific Aim #2 – Define the specific CNS cell type required to express the Db class I molecule that results in brain atrophy. The proposed research is innovative because it capitalizes on the first demonstration that brain atrophy is impacted by the immunologically relevant Db class I molecule. This strongly implies a role for specific types of inflammation, namely CD8 T cells, in promoting brain atrophy, a feature of neurological disease with unknown etiology. Furthermore, the proposed development of the transgenic mouse used will enable conditional silencing of the Db class I molecule expression in specific cell types in vivo. To accomplish these aims, we will employ: (a) flow cytometry, (b) behavioral studies, (c) high resolution confocal microscopy and immunohistochemistry, and (d) small mammal MRI and MR spectroscopy.

抽象的 脑萎缩，否则归类为CNS CNS神经退行性（CNS-ND），是神经病学的广告 像阿尔茨海默氏病，脑瘫，痴呆症，皮克病，亨廷顿氏病一样多样化的疾病，亨廷顿氏病， Krabbe病，多发性硬化症（MS），癫痫，脑炎，神经淋巴细胞和神经加剧。 萎缩发生在神经系统疾病中尚待完全定义。 神经炎症已被提出为CNS-ND的推定机制 不可逆，与认知和运动缺陷相关。 作为如此众多紧迫的神经含量的特征，必须开发模型系统 确定CNS-ND的细胞和分子基础。 在此提案中使用Theiler的主要进行性M.的病毒模型的CNS-ND 急性脑萎缩的模型，在FVB小鼠菌株中发现CNS-ND。 感染的FVB小鼠可以采用强大的转基因方法来定义脑萎缩的病因。 表达H-2DB（DB）I类分子的转基因FVB小鼠在期间获得新的CD8 T细胞反应 TMEV感染并具有早期发作的大脑萎缩。 神经炎症会促进CNS-ND。 独特的方法论，模型和试剂，我们计划追求以下两个AM： 特定的目标＃1-确定性CNS-ND通过CD8 T细胞响应介导。 特定目标＃2-定义表达DB I类分子所需的特定CNS单元类型 导致脑萎缩。 拟议的研究是创新的，因为它首先证明了大脑萎缩是 受IMNOGOLIOG与I级分子的影响。 炎症，即CD8 T细胞，在促进脑萎缩，这是神经病学疾病的特征 病因。 在体内特定细胞类型中DB I类表达的沉默。 就业：（a）流式囊肿，（b）行为研究，（c）高分辨率共聚焦显微镜和 免疫组织化学以及（D）小型哺乳动物MRI和MR光谱学。