Influenza, Inflammation, and Parkinson's Disease

流感、炎症和帕金森病

• 批准号: 8656453
• 负责人: RICHARD J SMEYNE
• 金额: $ 37.9万
• 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/8656453
• 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）：帕金森氏病的病因是多元的，从鉴定的遗传突变到严格的环境因果关系。一种已被证明会诱发帕金森氏症的环境药物是病毒，包括流感。我们的实验室和其他实验室表明，高度致病性的禽流感病毒H5N1是神经性的，可以诱导多种帕金森氏症病理学，包括DA神经元中DA表型的丧失，增加了免疫系统的激活和增加的磷酸化和增加的磷酸化和alpha--磷酸素的聚集。目前未知的是，我们观察到的诱发的帕金森病病理仅针对某些流感菌株（已知是神经性的菌株（H5N1）），还是也可以由不输入CNS的人引起，包括1918-H1N1流感病毒的经济体，并在西班牙造成的效果中均具有所含义，并且是对西班牙造成的效果。 H1N1流感病毒菌株（A/H1N1/CA/04/2009）最负责2009年大流行。我们还试图确定负责流感神经性的关键基因。在此应用中，我们提出了3个特定的 旨在研究流感在神经退行性疾病中的作用，集中在帕金森氏病中观察到的病理上。这些是：1）确定不是神经性神经性的A型流感菌株，并鉴定出赋予神经性神经性神经性的流感基因组中的基因，2）确定由神经性和非神经性静脉流感病毒构想的脑中植物疾病的神经性和非神经性型植物的脑部的免疫反应，以及3）其他类型的A流感病毒。这些研究的结果利用了神经性H5N1和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，它将允许我们识别该病毒中的关键成分，从而允许进入神经系统进入神经系统并了解外围感染如何发出外围感染的脑部脑部脑中的激活。在人类健康方面，这些研究将使我们能够预测当前（即H5N1和H1N1）以及未来新兴的流感菌株将如何影响CNS；以及识别允许开发治疗剂来干扰这些过程的靶标（已知和未知）。