权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Neural stem/progenitor cell fate: pathology and protection during CNS infections

神经干/祖细胞命运：中枢神经系统感染期间的病理学和保护

基本信息

批准号：
8812473
负责人：
LAUREN Alene O'DONNELL
金额：
$ 39.6万
依托单位：
DUQUESNE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8812473
关键词：
Acute Adult Affect Antiviral Agents Antiviral Response Arboviruses Behavioral Biological Assay Biological Models Brain Bystander Effect CD46 Antigen Cell Differentiation process Cell Line Cell Proliferation Cell physiology Cells Central Nervous System Infections Central Nervous System Viral Diseases Cessation of life Cognitive deficits Confocal Microscopy Cytomegalovirus Data Development Down-Regulation Elderly Encephalitis Family Flavivirus Flow Cytometry Functional disorder Goals HIV Health Herpesviridae Hippocampus (Brain)Human Immune Immune response Immune system Immunity Immunization Immunocompromised Host In Vitro Infection Inflammation Inflammation Mediators Inflammatory Interferon Type II Interferons Knock-out Knockout Mice Laboratories Link Measles virus Mediating Modality Modeling Molecular Mus Natural regeneration Neonatal Neuraxis Neurodegenerative Disorders Neuroglia Neurologic Neuron-Specific Enolase Neurons Pathology Pathway interactions Physiological Production Protein Family Proteins Public Health Research Role STAT protein STAT1 gene STAT3 gene Seizures Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Small Interfering RNA Staining method Stains Stem cells T cell response T-Lymphocyte Therapeutic Therapeutic Intervention Transgenic Mice Transgenic Organisms United States Up-Regulation Viral Virus Virus Diseases Virus Receptors Western Blotting adaptive immunity age related cell type cognitive function cytokine developmental disease in vivo inhibitor/antagonist innovation mouse model neonate nerve stem cell nervous system development neuroinflammation neuron loss neuropathology neurotropic neurotropic virus novel strategies programs promoter receptor relating to nervous system repaired research study stem therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Many diverse viruses cause devastating central nervous system (CNS) infections in the United States (e.g. herpesvirus, HIV, arboviruses), leading to severe encephalitis, long-term neurological sequelae (seizures, cognitive deficits, developmental disorders, etc.), and death. Though the immune system vigorously responds to the virus, CNS infections are associated with acute damage to neurons and loss of neural stem/progenitor cells (NSPCs). The immune response may even contribute to neuropathology through bystander effects on uninfected cells near the infection. For example, NSPCs are responsive to many pro-inflammatory mediators, which disrupt the production of new neurons by the NSPCs and potentially inhibit CNS repair. The interactions between the virus, the immune response, and NSPCs are not well understood, and therapeutic modalities for protecting NSPCs or modulating anti-viral immunity in the CNS are lacking. We have recently characterized the role of interferon-gamma (IFNγ), an anti-viral cytokine produced by immune cells, during CNS infections. We hypothesize that IFNγ drives NSPCs toward production of new glia instead of new neurons, which could have profound effects on CNS repair. Using a transgenic mouse model of neuron-restricted measles virus infection in the brain (CD46+ mice), we have found that IFNγ preserves the NSPC pool but is unable to protect newly-born neurons in infected neonatal mice. We also observed increased expression of astrocytic markers in IFNγ-treated NSPCs, suggesting that IFNγ drives NSPCs toward production of new glia as opposed to new neurons. Importantly, in the CD46+ model, the virus is restricted to mature neurons, allowing for the analysis of inflammation on NSPCs without the confounding effects of direct NSPC infection. In Aim 1, we determine the role of critical components of the anti-viral response in altering NSPC proliferation and differentiation in neonatal and adult mice. We have crossed the CD46+ mice to a variety of immune-knockout backgrounds to study specifically the role of IFNγ and the immune cells that produce the majority of IFNγ (T-cells) in NSPC dysfunction. Thus, these experiments are distinctly suited to determine the effects of the anti-viral immune response on NSPCs during an infection. In Aim 2, we define the role of pro-inflammatory signaling molecules in cell fate decisions during IFNγ treatment in vitro and during an in vivo infection. We have established in vitro culture conditions for primary wildtype and knockout NSPCs, which we will use with pharmacological inhibitors and siRNA knockdown to identify signaling molecules that are involved in IFNγ signaling and cell fate choices. These studies are innovative because the role of the anti-viral immune response in NSPC dysfunction will be defined independently from the direct effects of the virus. Moreover, these studies will identify pro-inflammatory signaling molecules that dictate cell fate choice in NSPCs, establish a model system for defining and ameliorating the long-term neurological deficits from CNS infections, and propose a new approach for studying the effects of neuroinflammation on CNS development and repair.

描述（由申请人提供）：许多不同的病毒在美国引起毁灭性的中枢神经系统（CNS）感染（例如疱疹病毒、艾滋病毒、虫媒病毒），导致严重脑炎、长期神经系统后遗症（癫痫发作、认知缺陷、发育障碍等）和死亡。尽管免疫系统对病毒反应强烈，但中枢神经系统感染与神经元的急性损伤和神经干/祖细胞 (NSPC) 的损失有关。免疫反应甚至可能通过对感染附近未感染细胞的旁观者影响而促进神经病理学。例如，NSPC 对许多促炎介质有反应，这些介质会破坏 NSPC 产生新神经元，并可能抑制 CNS 修复。病毒、免疫反应和 NSPC 之间的相互作用尚不清楚，并且缺乏保护 NSPC 或调节 CNS 抗病毒免疫的治疗方式。我们最近描述了干扰素γ（IFNγ）（一种由免疫细胞产生的抗病毒细胞因子）在中枢神经系统感染过程中的作用。我们假设 IFNγ 驱动 NSPC 产生新的神经胶质细胞而不是新的神经元，这可能对 CNS 修复产生深远的影响。使用大脑中神经元限制性麻疹病毒感染的转基因小鼠模型（CD46+小鼠），我们发现IFNγ保留了NSPC库，但无法保护受感染的新生小鼠中的新生神经元。我们还观察到 IFNγ 处理的 NSPC 中星形胶质细胞标记物的表达增加，这表明 IFNγ 驱动 NSPC 产生新的神经胶质细胞，而不是新的神经元。重要的是，在 CD46+ 模型中，病毒仅限于成熟神经元，因此可以分析 NSPC 上的炎症，而不会受到直接 NSPC 感染的混淆影响。在目标 1 中，我们确定了抗病毒反应的关键成分在改变新生和成年小鼠 NSPC 增殖和分化中的作用。我们将 CD46+ 小鼠与多种免疫敲除背景进行杂交，以专门研究 IFNγ 和产生大部分 IFNγ 的免疫细胞（T 细胞）在 NSPC 功能障碍中的作用。因此，这些实验非常适合确定感染期间抗病毒免疫反应对 NSPC 的影响。在目标 2 中，我们定义了促炎信号分子在体外 IFNγ 治疗期间和体内感染期间细胞命运决定中的作用。我们已经建立了原代野生型和敲除型 NSPC 的体外培养条件，我们将其与药理学抑制剂和 siRNA 敲低一起使用，以鉴定参与 IFNγ 信号传导和细胞命运选择的信号分子。这些研究具有创新性，因为抗病毒免疫反应在 NSPC 功能障碍中的作用将独立于病毒的直接影响来定义。此外，这些研究将鉴定决定 NSPC 细胞命运选择的促炎信号分子，建立一个模型系统来定义和改善中枢神经系统感染引起的长期神经功能缺损，并提出一种研究神经炎症对中枢神经系统发育和修复影响的新方法。