Retrograde Dystrophic Influence of IFN-gamma on Neurons

IFN-γ 对神经元的逆行营养不良影响

• 批准号: 6777552
• 负责人: Pamela J Lein
• 金额: $ 24.84万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-16 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6777552
• 关键词: SDS polyacrylamide gel electrophoresis; autoradiography; axon; biological signal transduction; biomarker; dendrites; enzyme linked immunosorbent assay; genetically modified animals; inflammation; interferon gamma; laboratory mouse; laboratory rat; major histocompatibility complex; neuroanatomy; neuropathology; nitric oxide synthase; parainfluenza virus type 1; polymerase chain reaction; soma; superior cervical ganglion; synapses; western blottings

DESCRIPTION (provided by applicant): Inflammation is a common etiological factor in the pathogenesis of diverse neurological diseases; however, mechanisms by which inflammation causes neural dysfunction are not well understood. We hypothesize that the pro-inflammatory gamma interferon (IFNgamma) contributes to inflammation-associated neuropathology by acting directly on neurons to induce dendrite retraction and synapse loss. This hypothesis is derived from observations that (1) dendritic atrophy and elevated IFNgamma are coincidental in inflammatory reactions caused by viral infection, trauma or ischemia, in chronic inflammatory or viral diseases such as multiple sclerosis or HIV and in neurodegenerative diseases such as Alzheimer's and Parkinson's disease; and (2) dendritic atrophy has been linked to neural dysfunction. We have recently shown that IFNgamma causes dendritic retraction and synaptic loss in cultured peripheral and central neurons in the absence of adverse effects on cell viability or axons. What is not known is whether IFNgamma elicits the same response in vivo, and if IFNgamma generated by peripheral inflammatory events can initiate dystrophic signals that are propagated back to the soma. The significance of the latter is suggested by observations that many neuropathological inflammatory lesions are largely restricted to white matter or target tissues. Using neurons of the superior cervical ganglion (SCG) as a model system, we will address the following specific aims: 1) Determine if systemic administration of lFNgamma is sufficient to cause dendrite retraction and synapse loss in vivo; 2) Assess whether IFNgamma signaling from distal axons is sufficient to cause dendritic retraction in neurons grown in compartmented chambers; and 3) Determine if peripheral inflammation causes dendritic retraction in vivo and if IFNgamma is necessary for this effect. Aim 3 will be accomplished by quantifying dendritic arborization in SCG neurons that innervate airways in wildtype, IFNgamma-/- and IFNgamma Ralpha -/- mice following airway infection with Sendai parainfluenza virus. SCG neurons that project to airways will be identified by retrograde labeling with Fast Blue, and dendritic arbors will be visualized using DiI labeling. Major histocompatibility complex-I and nitric oxide synthase expression will be monitored in SCG as biomarkers of exposure to pharmacologically active concentrations of IFNgamma. These studies will provide significant insights regarding the effect of pro-inflammatory cytokines on neural circuitry, and identify a novel mechanism for conveying information about peripheral injury or inflammation to distal brain loci.

描述（由申请人提供）：炎症是多种神经系统疾病发病机理的常见病因。但是，炎症引起神经功能障碍的机制尚不清楚。我们假设促炎性伽马干扰素（IFNGAMMA）通过直接作用于神经元来诱导树突缩回和突触丧失来促进与炎症相关的神经病理学。 This hypothesis is derived from observations that (1) dendritic atrophy and elevated IFNgamma are coincidental in inflammatory reactions caused by viral infection, trauma or ischemia, in chronic inflammatory or viral diseases such as multiple sclerosis or HIV and in neurodegenerative diseases such as Alzheimer's and Parkinson's disease; （2）树突状萎缩与神经功能障碍有关。我们最近表明，在没有对细胞活力或轴突的不良影响的情况下，IFNGAMMA会导致培养的外周和中央神经元的树突缩回和突触丧失。尚不清楚的是，Ifngamma是否在体内引起相同的反应，以及外周炎性事件产生的IFNGAMMA是否可以引起疾病的疾病信号，这些信号传播回SOMA。观察到许多神经病理炎症病变在很大程度上仅限于白质或靶组织，这表明了后者的意义。 使用上颈神经节（SCG）的神经元作为模型系统，我们将解决以下特定目的：1）确定LFNGAMMA的全身施用是否足以引起树突缩回和体内突触损失； 2）评估远端轴突的IFNGAMMA信号传导是否足以引起隔室中生长的神经元的树突回缩； 3）确定周围炎症是否会导致体内树突缩回，以及是否需要IFNGAMMA才能为此作用。 AIM 3将通过量化Wildtype，Ifngamma - / - 和Ifngamma ralpha - / - 小鼠的SCG神经元中的树突状树皮化来实现，并在Sendai Parainfluenza病毒中呼吸道感染后。将通过快速蓝色的逆行标记来识别向气道投射的SCG神经元，并且将使用DII标签可视化树突状乔木。主要的组织相容性复合物I和一氧化氮合酶的表达将在SCG中监测，作为暴露于IFNGAMMA的药理活动浓度的生物标志物。这些研究将提供有关促炎细胞因子对神经回路的影响的重要见解，并确定一种新的机制，用于传达有关外围损伤或炎症到远端大脑基因座的信息。