Influenza, Inflammation, and Parkinson's Disease

描述（由申请人提供）：帕金森病的病因是多方面的，从确定的基因突变到严格的环境原因。一种已被证明能诱发帕金森症的环境因素是病毒，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H5 N1是嗜神经的，并且可以诱导许多帕金森病病理，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是否仅特异于某些流感病毒株（已知是嗜神经性的（H5 N1）），或也可由不进入CNS的那些引起，包括1918-H1N1流感病毒是西班牙流感的罪魁祸首，与von Economo脑病和H1N1流感病毒株有关（A/H1N1/CA/04/2009）是造成2009年大流行病的主要原因。我们还试图确定负责流感嗜神经性的关键基因。在本申请中，我们提出了3个具体的 旨在研究流感在神经退行性疾病中的作用，集中在帕金森病中观察到的病理学。这些是：1）鉴定嗜神经性/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）确定由嗜神经性和非嗜神经性流感病毒引发的脑中的免疫应答，和3）确定由H5 N1 A型流感病毒诱导的帕金森病病理是否与其他A型流感病毒共同。这些研究的结果利用了嗜神经性H5 N1和1918-H1N1以及2009 H1N1流感病毒之间产生的一系列独特的嵌合流感病毒，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激活大脑中的免疫反应。在人类健康方面，这些研究将使我们能够预测当前（即H5 N1和H1N1）和未来新出现的流感病毒株将如何影响CNS;以及确定允许开发治疗剂以干扰这些过程的靶点（已知和未知）。

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.