Influenza, Inflammation, and Parkinson's Disease

流感、炎症和帕金森病

• 批准号: 8434805
• 负责人: RICHARD J SMEYNE
• 金额: $ 36.94万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434805
• 关键词: 3,4-Dihydroxyphenylacetic Acid; Alzheimer' s Disease; B-Lymphocytes; Brain; Centers for Disease Control and Prevention (U.S.); Characteristics; Chemicals; Clinical; Conscious; Corpus striatum structure; Cranial Nerves; Deposition; Development; Disorientation; Dopamine; Elements; Encephalitis; Encephalopathies; Etiology; Face; Future; Ganglia; Gene Mutation; General Population; Genes; Genome; Growth Factor; Health; High Pressure Liquid Chromatography; Human; Immune response; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Intranasal Administration; Long-Term Effects; Measures; Medical; Mesentery; Messenger RNA; Microglia; Monoclonal Antibodies; Mus; NP protein; Nervous system structure; Neurodegenerative Disorders; Neurologic; Neurotropism; Olfactory Nerve; Outcome Study; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Pathology; Peripheral; Persons; Phenotype; Phosphorylation; Population; Predisposition; Process; Property; Proteins; Public Health; Reaction; Reporting; Rest; Role; Route; Seizures; Series; Serotonin; Signal Transduction; Spinal Cord; Sympathetic Ganglia; Symptoms; Systemic infection; T-Lymphocyte; Therapeutic Agents; Time; Transgenic Mice; Travel; Trigeminal nerve structure; Type A Influenza; Vagus nerve structure; Vertebral column; Viral; Virus; Work; alpha synuclein; base; chemokine; cytokine; disorder prevention; dopaminergic neuron; environmental agent; flu; follow-up; influenza outbreak; influenza virus strain; influenzavirus; neurotropic; pandemic disease; positional cloning; protein aggregate; relating to nervous system; research study; response; spinal nerve posterior root; swine flu; tau-1

DESCRIPTION (provided by applicant): The etiology of Parkinson's disease is multivariate, ranging from identified genetic mutations to strict environmental causation. One environmental agent that has been shown to induce Parkinsonism is virus, including influenza. Our lab, and others, has shown that the highly pathogenic avian influenza virus, H5N1, is neurotropic and can induce a number of Parkinsonism pathologies including loss of the DA phenotype in DA neurons, increased activation of the immune system and increased phosphorylation and aggregation of alpha- synuclein. What is unknown, at this time, is whether the induced Parkinsonian pathologies that we observed are specific to only certain strains of influenza (those known to be neurotropic (H5N1)), or can also be induced by those that do not enter the CNS, including the 1918-H1N1 influenza virus that was responsible for the Spanish flu and has been implicated in von Economo's encephalopathy and the H1N1 influenza virus strain (A/H1N1/CA/04/2009) most responsible for the 2009 pandemic. We also seek to determine the critical gene(s) responsible for influenza neurotropism. In this application, we propose 3 specific aims to investigate the role of influenza in neurodegenerative disease, concentrating on pathologies observed in Parkinson's disease. These are: 1) Identify strains of Type A Influenza that are/are not neurotropic, and identify the gene(s) within the influenza genome that confer neurotropism, 2) Determine the immune response in brain initiated by neurotropic and non-neurotropic influenza viruses, and 3) Determine if the parkinsonian pathologies induced by the H5N1 Type A Influenza virus are common to other Type A influenza viruses. The results of these studies, which utilize a unique series of chimeric influenza viruses generated between the neurotropic H5N1 and 1918-H1N1and 2009 H1N1 influenza viruses, will allow us to identify the key components within the virus that allow entry into the nervous system and understand how peripheral infection can signal activation of the immune response in brain. In terms of human health, these studies will allow us to predict how current (i.e. H5N1 and H1N1) and future emerging influenza strains will impact the CNS; as well as identify targets (both known and unknown) that allow for development of therapeutic agents to interfere with these processes.

描述（由申请人提供）：帕金森病的病因是多因素的，从已识别的基因突变到严格的环境因果关系。已证明可诱发帕金森症的一种环境因素是病毒，包括流感。我们的实验室和其他实验室已经表明，高致病性禽流感病毒 H5N1 具有嗜神经性，可诱发多种帕金森病病理，包括 DA 神经元中 DA 表型的丧失、免疫系统的激活增加以及 α-突触核蛋白的磷酸化和聚集增加。目前尚不清楚的是，我们观察到的诱发帕金森病病理是否仅针对某些流感病毒株（已知为神经性流感病毒（H5N1）），或者也可以由那些不进入中枢神经系统的流感病毒株诱发，包括导致西班牙流感并与冯·埃科诺莫脑病和流感病毒有关的 1918-H1N1 流感病毒。 H1N1 流感病毒株 (A/H1N1/CA/04/2009) 对 2009 年大流行负有最大责任。我们还试图确定导致流感神经性的关键基因。在此应用中，我们提出了 3 个具体方案 旨在研究流感在神经退行性疾病中的作用，重点关注帕金森病中观察到的病理学。这些是：1) 鉴定嗜神经性或非嗜神经性的 A 型流感毒株，并鉴定流感基因组中赋予嗜神经性的基因，2) 确定嗜神经性和非嗜神经性流感病毒在大脑中引发的免疫反应，以及 3) 确定 H5N1 甲型流感病毒诱发的帕金森病病理是否常见 其他甲型流感病毒。这些研究利用嗜神经性 H5N1 与 1918-H1N1 和 2009 H1N1 流感病毒之间产生的一系列独特的嵌合流感病毒，其结果将使我们能够识别病毒内允许进入神经系统的关键成分，并了解外周感染如何发出大脑免疫反应激活的信号。就人类健康而言，这些研究将使我们能够预测当前（即 H5N1 和 H1N1）和未来新出现的流感病毒株将如何影响中枢神经系统；以及确定允许开发干扰这些过程的治疗剂的目标（已知和未知）。