STAT3 and astrogliosis in Alexander disease

亚历山大病中的 STAT3 和星形胶质细胞增生

• 批准号: 8952618
• 负责人: Tracy Hagemann
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8952618
• 关键词: Acute; Affect; Alexander Disease; Alleles; Animals; Astrocytes; Automobile Driving; Binding; Biological Process; Brain; Brain Stem; Brain region; Cerebellum; Cervical spinal cord structure; Chronic; Corpus Callosum; Data; Data Analyses; Disease; Disease model; Feedback; Fiber; Functional disorder; Genes; Genetic; Genetic Models; Glial Fibrillary Acidic Protein; Gliosis; Goals; Heterogeneity; Hippocampus (Brain); Immune; Injury; Intermediate Filaments; JAK2 gene; Knockout Mice; Lead; Microarray Analysis; Minor; Modeling; Molecular; Mus; Mutation; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Point Mutation; Population; Property; Prosencephalon; Proteins; Rare Diseases; Role; STAT protein; STAT3 gene; Signal Transduction; Stress; System; Testing; Therapeutic; Toxic effect; Transactivation; Transcript; Transducers; astrogliosis; biological adaptation to stress; cell type; driving force; early onset; frontal lobe; genetic approach; gliogenesis; hindbrain; inhibitor/antagonist; insight; interest; mouse model; mutant; novel; olfactory bulb; promoter; protein aggregate; protein aggregation; protein expression; public health relevance; research study; response; therapeutic target; transcription factor; young adult

 DESCRIPTION (provided by applicant): Alexander disease (AxD) is caused by dominant point mutations in the gene encoding glial fibrillary acidic protein (GFAP), an intermediate filament expressed in astrocytes of the central nervous system (CNS). A major factor in the pathology of AxD is astrogliosis and the concomitant increase in GFAP expression that exacerbates protein accumulation and GFAP toxicity. However the direct cause of GFAP transactivation is not known. In Gfap+/R236H mouse models of AxD, reactive astrocytes with GFAP aggregates are present throughout forebrain regions including hippocampus, corpus callosum and olfactory bulb, while hindbrain regions show minor or no increase in GFAP. Our recent findings show that the transcription factor and signal transducer STAT3, well known as a regulator of gliogenesis, astrogliosis, and GFAP expression, is also activated in astrocytes in AxD. In the mouse models of AxD, STAT3 activation coincides with astrogliosis and increased GFAP in forebrain astrocytes, with little activation in hindbrain regions. In this proposal, to understand the role o STAT3 in astrogliosis and the heterogeneous response to mutant GFAP, we will employ our Gfap+/R236H mice to determine whether STAT3 activation is necessary to sustain chronic gliosis, and to identify astrocyte specific gene networks underlying the differential response to the same genetic insult. In Specific Aim 1, we will test whether STAT3 is part of a positive feedback loop that drives GFAP expression and astrogliosis in AxD. Both genetic and pharmacological inhibition of the JAK2/STAT3 pathway will be used to determine its contribution to astrocyte activation and increased GFAP expression. First, we will cross Gfap+/R236H and STAT3 knockout mice to analyze whether decreased STAT3 levels result in a corresponding decrease in GFAP. In a second set of experiments, the JAK2 inhibitor AZD1480 will be used to treat both young and adult Gfap+/R236H mice and determine whether blocking STAT3 activation can reduce gliosis and GFAP accumulation. Our AxD mouse models have been well characterized and further analysis of established phenotypes will show whether reducing STAT3 affects the stress response and other cell types in the CNS. In Specific Aim 2, we will focus on regional heterogeneity in STAT3 activation and astrogliosis. Translational profiling will be used to isolate astrocyte specific transcripts and identify the gene networks that differentially regulae gliosis in forebrain versus hindbrain astrocyte populations. In addition to identifying pathways regulating STAT3 activation, these experiments will define new mechanisms controlling astrocyte reactivity in different brain regions. Given the current interest in astrocytes as therapeutic targets in other proteinopathies and neurodegenerative disease, these studies will provide insight into how region specific pathology may impact therapeutic strategy. This will be the first study to identify the intrinsic differences in regional astrocyte populations that contro reactive gliosis in a genetic model of neurodegeneration.

 描述（由申请方提供）：亚历山大病（AxD）是由编码胶质细胞酸性蛋白（GFAP）的基因中的显性点突变引起的，GFAP是一种在中枢神经系统（CNS）星形胶质细胞中表达的中间丝。AxD病理学中的一个主要因素是星形胶质细胞增生和伴随的GFAP表达增加，其加剧了蛋白质积累和GFAP毒性。然而，GFAP反式激活的直接原因尚不清楚。在AxD的GFap+/R236 H小鼠模型中，具有GFAP聚集体的反应性星形胶质细胞存在于整个前脑区域，包括海马、胼胝体和嗅球，而后脑区域显示GFAP轻微增加或没有增加。我们最近的研究结果表明，转录因子和信号转导STAT 3，众所周知的胶质细胞生成，星形胶质细胞增生和GFAP表达的调节剂，也被激活的星形胶质细胞在AxD。在AxD小鼠模型中，STAT 3激活与前脑星形胶质细胞中的星形胶质细胞增生和GFAP增加一致，而后脑区域几乎没有激活。在这个提议中，为了理解STAT 3在星形胶质细胞增生中的作用和对突变型GFAP的异质性反应，我们将使用我们的GFAP+/R236 H小鼠来确定STAT 3激活是否是维持慢性胶质细胞增生所必需的，并鉴定星形胶质细胞特异性基因网络对相同遗传损伤的差异反应。在具体目标1中，我们将测试STAT 3是否是驱动AxD中GFAP表达和星形胶质细胞增生的正反馈回路的一部分。JAK 2/STAT 3通路的遗传和药理学抑制将用于确定其对星形胶质细胞活化和GFAP表达增加的贡献。首先，我们将Gfap+/R236 H和STAT 3敲除小鼠杂交，以分析STAT 3水平降低是否导致GFAP相应降低。在第二组实验中，JAK 2抑制剂AZD 1480将用于治疗年轻和成年Gfap+/R236 H小鼠，并确定阻断STAT 3激活是否可以减少胶质增生和GFAP积累。我们的AxD小鼠模型已经得到了很好的表征，对已建立的表型的进一步分析将显示减少STAT 3是否会影响CNS中的应激反应和其他细胞类型。在具体目标2中，我们将重点关注STAT 3激活和星形胶质细胞增生的区域异质性。翻译谱将用于分离星形胶质细胞特异性转录物，并鉴定在前脑星形胶质细胞群体与后脑星形胶质细胞群体中差异调节神经胶质增生的基因网络。除了确定调节STAT 3激活的途径外，这些实验还将确定控制不同脑区星形胶质细胞反应性的新机制。鉴于目前对星形胶质细胞作为其他蛋白质病和神经退行性疾病的治疗靶点的兴趣，这些研究将深入了解区域特异性病理学如何影响治疗策略。这将是第一个研究，以确定内在的差异，在区域星形胶质细胞群体控制反应性胶质细胞增生的遗传模型的神经退行性疾病。