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.

摘要 脑萎缩，也被归类为中枢神经系统神经变性（CNS-ND），是神经系统的常见特征 多种疾病，如阿尔茨海默病、脑瘫、痴呆、皮克病、亨廷顿病， Krabbe病、多发性硬化症（MS）、癫痫、脑炎、神经梅毒和神经艾滋病。大脑如何 神经系统疾病中发生的萎缩仍有待完全定义。但是，神经损伤，感染， 和神经炎症被认为是CNS-ND的发病机制。CNS-ND总体保持 不可逆的，并与认知和运动缺陷相关。此外，脑萎缩的观察 作为如此多紧迫的神经疾病的特征，需要开发模型系统， 确定CNS-ND的细胞和分子基础。我们的研究团队最近发表了第一项研究 CNS-ND使用Theiler的病毒模型的主要进展MS。在这项建议中，我们介绍了一种新的 FVB小鼠品系中存在的急性脑萎缩模型。TMEV中CNS-ND的发现 感染FVB的小鼠能够使用强大的转基因方法来确定脑萎缩的病因。 表达H-2Db（Db）I类分子的转基因FVB小鼠在免疫过程中获得新的CD 8 T细胞应答。 TMEV感染并有早发性脑萎缩。我们建议测试我们的中心假设， 神经炎症有助于CNS-ND。基于可靠的初步数据，并通过使用我们的 独特的方法、模型和试剂，我们计划追求以下两个目标： 具体目标#1 -确定CNS-ND通过CD 8 T细胞应答介导的程度。 具体目标#2 -定义表达Db I类分子所需的特定CNS细胞类型， 导致脑萎缩 这项拟议中的研究是创新的，因为它利用了第一个证明，即脑萎缩是 受免疫学相关Db I类分子的影响。这强烈暗示了特定类型的 炎症，即CD 8 T细胞，在促进脑萎缩，神经系统疾病的一个特点，未知 病因学此外，所用转基因小鼠的拟议开发将使条件 体内特定细胞类型中Db I类分子表达的沉默。为了实现这些目标，我们将 采用：（a）流式细胞术，（B）行为研究，（c）高分辨率共聚焦显微镜和 免疫组织化学，和（d）小哺乳动物MRI和MR光谱。