The impact of systemic viral infections on the innate immune response in the brain in chronic neurodegeneration

慢性神经退行性疾病中全身病毒感染对大脑先天免疫反应的影响

• 批准号: G1100591/1
• 负责人: Jean Manson
• 金额: $ 71.12万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1100591%2F1
• 关键词: impact; systemic; viral; infections; innate

Cells known as macrophages are our first line of defence against injury and infection. It is well recognised that they may exist in many different functional states: they not only detect and kill invading organisms but are involved in tissue repair. In the brain there is a population of resident tissue macrophages known as the microglia, which is normally kept under tight control by the brain microenvironment. However, during brain injury and disease they become activated. As the population of the UK and developing world lives longer so the prevalence of chronic neurodegenerative diseases is increasing with profound social and economic consequences. The most common form of chronic neurodegenerative disease, Alzhemier?s disease, is associated with accumulation of misfolded protein in the brain, widespread neuronal degeneration and activation of microglia. It is not clear whether the observed increase in microglia activation has beneficial effects by preventing misfolded protein accumulation or whether their activity contributes to the pathology of the disease. Recent data suggests that systemic inflammation caused by bacterial or viral infections in individuals with Alzheimer?s disease is associated with accelerated cognitive decline and exacerbation of behavioural problems. It is known that signalling of systemic inflammation to the brain involves microglia. In this proposal we will use our well-defined laboratory model of chronic progressive neurodegeneration, prion disease in mice, to investigate how a systemic viral infection impacts on the activated microglia in the diseased brain and whether this affects the progression of neurodegeneration. We will use behavioural assays and neuropathology to investigate how the viral infection alters disease progression. We will use molecular, cellular and biochemical techniques to study how the viral infection alters the state of activation of the microglia in the brain. We will use state of the art bio-information techniques to compare our data on microglia activation states with data about genes that make individuals susceptible to Alzheimer?s disease. In understanding the role of microglia we can help to establish the mechanisms causing brain damage thus facilitating development of future therapeutic approaches for chronic neurodegenerative disease involving the accumulation of misfolded protein disease. If systemic infections are driving disease progression they can be treated to delay disease progression and improve the quality of life of patients with neurodegenerative disease.

被称为巨噬细胞的细胞是我们抵御损伤和感染的第一道防线。众所周知，它们可能存在于许多不同的功能状态：它们不仅探测和杀死入侵的生物体，而且参与组织修复。在大脑中有一群被称为小胶质细胞的常驻组织巨噬细胞，它们通常受到大脑微环境的严格控制。然而，在脑损伤和疾病期间，它们被激活。随着英国和发展中国家人口寿命的延长，慢性神经退行性疾病的患病率也在增加，带来了深远的社会和经济后果。最常见的慢性神经退行性疾病阿尔茨海默病？S疾病，与大脑中错误折叠蛋白的积累、广泛的神经元变性和小胶质细胞的激活有关。目前尚不清楚观察到的小胶质细胞激活的增加是否通过防止错误折叠的蛋白质积累而产生有益的影响，或者它们的活性是否有助于疾病的病理。最近的数据表明，阿尔茨海默病患者由细菌或病毒感染引起的全身性炎症。S病与认知能力加速下降和行为问题加剧有关。众所周知，全身性炎症向大脑发出的信号涉及小胶质细胞。在这项提议中，我们将使用我们定义良好的慢性进行性神经退行性疾病的实验室模型，小鼠朊病毒疾病，来研究全身性病毒感染如何影响病变大脑中活化的小胶质细胞，以及这是否影响神经退行性疾病的进展。我们将使用行为分析和神经病理学来研究病毒感染如何改变疾病进展。我们将使用分子、细胞和生化技术来研究病毒感染如何改变大脑小胶质细胞的激活状态。我们将使用最先进的生物信息技术将我们的小胶质细胞激活状态数据与使个体易患阿尔茨海默病的基因数据进行比较。年代的疾病。通过了解小胶质细胞的作用，我们可以帮助建立导致脑损伤的机制，从而促进未来治疗涉及错误折叠蛋白积累的慢性神经退行性疾病的方法的发展。如果全身性感染是疾病进展的驱动因素，可以对其进行治疗，以延缓疾病进展并改善神经退行性疾病患者的生活质量。