Mechanisms of Virus Induced Motor Neuron Injury and Treatment of Viral Myelitis

病毒引起的运动神经元损伤的机制及病毒性脊髓炎的治疗

• 批准号: 7486007
• 负责人: Stephanie Anne Schittone
• 金额: $ 3.14万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486007
• 关键词: Acute; Acyclovir; Amyotrophic Lateral Sclerosis; Antiviral Agents; Apoptosis; Apoptotic; Brain; Calpain; Caspase; Caspase Inhibitor; Cell Cycle; Cell Death; Cells; Central Nervous System Diseases; Central Nervous System Viral Diseases; Cessation of life; DNA Damage; DNA Repair; Development; Disease; Disease Outcome; Effectiveness; Encephalitis; Endopeptidases; Event; Experimental Models; Free Radical Scavengers; Gene Chips; Genes; Gliosis; Goals; Heart; Human poliovirus; Immunohistochemistry; Infection; Inflammation; Injury; Investigation; Knowledge; Lasers; Lead; Measures; Modeling; Morbidity - disease rate; Motor Neurons; Mus; Myelitis; Neonatal; Nervous System Trauma; Neuraxis; Neurons; Numbers; Oligonucleotides; Outcome; Oxidative Stress; Paralysed; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Polioviruses; Population; Public Health; RNA; Rabies virus; Reoviridae Infections; Reovirus; Reporting; Research; Role; Signal Pathway; Signal Transduction; Simplexvirus; Source; Spinal; Spinal Cord; Spinal cord injury; Staining method; Stains; Stress; Study models; Testing; Therapeutic Uses; Time; Tissues; Translating; Treatment Protocols; Viral; Viral Pathogenesis; Virus; Virus Diseases; West Nile virus; Western Blotting; Work; activating transcription factor; brain tissue; cell type; combinatorial; design; improved; in vivo; killings; laser capture microdissection; mortality; motor neuron injury; nervous system disorder; neuron apoptosis; neurotropic virus; phenylmethylpyrazolone; quinoline; quinoline-val-asp(OMe)-CH2-OPH; response; therapy design

DESCRIPTION (provided by applicant): The primary goal of this research is to elucidate the mechanism of Reovirus induced spinal cord injury and to identify effective strategies to improve disease outcome. Reovirus infection of the spinal cord includes infection of motor neurons and results in acute flaccid paralysis. Reovirus infection of the brain is reported to induce apoptosis of infected neurons and activate transcription factors. Currently, the mechanisms of Reovirus injury to the spinal cord are poorly defined. Injury due to Reovirus infection of the spinal cord will be evaluated by immunohistology and western blot for injury mechanisms in Aim 1. Analysis will include markers of apoptosis, oxidative stress, inflammation, and calpain activation. In Aim 2, mechanistic differences between brain and spinal neuronal infection will be elucidated using apoptotic and DNA damage pathway specific oligo-gene arrays using RNA isolated from Laser Capture Microdissected neurons from infected and uninfected tissue. LCM will allow us to examine the reovirus induced transcriptional neuronal response from neurons within CNS tissue. Identification of the role of caspase proteases and oxidative stress, which are known to be up regulated in neurological injuries, will be examined further in reovirus spinal cord injury by treating mice with specific inhibitors of caspase and free radical scavengers in Aim 3. These treatments are expected to improve disease outcome of infected mice, as measured by decreases in injury mechanism markers and locomotor function. PUBLIC HEALTH RELEVANCE: This work will increase knowledge of the ways viruses interact with cells in the central nervous system (CNS). Improving the understanding of how viruses cause neurological disorders will allow advances in treatment design for illnesses caused by viral infection of the CNS. Some treatment options, outside antivirals, will be tested during the proposed work.

描述（由申请人提供）：本研究的主要目标是阐明呼肠孤病毒引起脊髓损伤的机制，并确定改善疾病结果的有效策略。脊髓呼肠孤病毒感染包括运动神经元感染并导致急性弛缓性麻痹。据报道，大脑的呼肠孤病毒感染会诱导受感染神经元的凋亡并激活转录因子。目前，呼肠孤病毒损伤脊髓的机制尚不清楚。将通过免疫组织学和蛋白质印迹来评估目标 1 中的损伤机制，以评估呼肠孤病毒感染引起的脊髓损伤。分析将包括细胞凋亡、氧化应激、炎症和钙蛋白酶激活的标记。在目标 2 中，将使用从感染和未感染组织的激光捕获显微解剖神经元中分离出的 RNA，使用细胞凋亡和 DNA 损伤途径特异性寡基因阵列来阐明大脑和脊髓神经元感染之间的机制差异。 LCM 将使我们能够检查呼肠孤病毒诱导的中枢神经系统组织内神经元的转录神经元反应。已知半胱天冬酶蛋白酶和氧化应激在神经损伤中上调，将通过在目标 3 中用特异性半胱天冬酶抑制剂和自由基清除剂治疗小鼠，在呼肠孤病毒脊髓损伤中进一步研究其作用。这些治疗方法是预计可以改善受感染小鼠的疾病结果，通过损伤机制标记物和运动功能的减少来衡量。公共卫生相关性：这项工作将增加人们对病毒与中枢神经系统 (CNS) 细胞相互作用方式的了解。提高对病毒如何引起神经系统疾病的了解将有助于中枢神经系统病毒感染引起的疾病的治疗设计取得进展。除抗病毒药物外，一些治疗方案将在拟议工作期间进行测试。