Mechanisms of Apoptosis in Virus-Infected Neurons

病毒感染神经元的凋亡机制

• 批准号: 8260229
• 负责人: John David Beckham
• 金额: $ 14.15万
• 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: 2008-06-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260229
• 关键词: Acyclovir; Apoptosis; Beta Cell; Brain; Cell Death; Cells; Central Nervous System Viral Diseases; Cessation of life; Clinical; Data; Development; Disease; Encephalitis; Environment; Event; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Herpes encephalitis; Human; Infection; Injury; Ligands; MAP Kinase Signaling Pathways; Mediating; Meningitis; Mentored Clinical Scientist Development Award (K08); Mentors; Methods; Modeling; Molecular Genetics; Morbidity - disease rate; Mus; Myelitis; N-terminal; Neonatal; Neurodegenerative Disorders; Neurons; Outcome; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Play; Professional Education; Protein Analysis; Regulation; Reoviridae Infections; Reovirus; Resources; Role; Sampling; Scientist; Signal Pathway; Signal Transduction; Simplexvirus; Smad Proteins; Smad protein; Spinal Cord; System; Techniques; Therapeutic; Time; Training; Transforming Growth Factor beta; Transforming Growth Factors; Viral; Viral Encephalitis; Viral Pathogenesis; Virus; Virus Diseases; West Nile virus; base; brain tissue; central nervous system injury; effective therapy; human disease; improved; insight; killings; laser capture microdissection; mortality; mouse model; mutant; neuron apoptosis; neuron loss; neurotropic virus; novel; receptor; research and development; skills; stress-activated protein kinase 1; transcription factor

DESCRIPTION (provided by applicant): Neurotropic viruses are important causes of morbidity and mortality throughout the world. The lack of therapeutic options for these diseases is driven by the paucity of understanding of the mechanisms by which neurotropic viruses cause disease. We propose to study the mechanisms responsible for viral-induced neuronal death. Based on our preliminary data, we will evaluate the roles of c-Jun N-terminal kinase (JNK) and transforming growth factor (TGF) -beta signaling during viral infection of primary cortical neurons and in the CMS of a mouse encephalitis model. Once these pathways are characterized in the reovirus model of encephalitis, we also propose to examine these events in human brain tissue obtained from patients infected with West Nile virus and herpes simplex virus. The specific role of these signaling pathways in viral-induced neuronal death is not known. In this application, we plan to characterize the role of JNK and TGF-beta signaling in virus-induced neuronal apoptosis and CNS injury in mice using multiple methods of protein analysis, viral manipulation, viral mutants, gene array analysis, real time-PCR, and laser-capture microdissection techniques. Human samples of brain tissue will then be evaluated using the techniques used for study in the reovirus model of infection. The study of mechanisms responsible for viral-induced cell death is critical to the development of new targeted therapies and neuroprotective strategies for viral infections of the brain and spinal cord. No effective therapy currently exists for West Nile virus infection and the discovery for new therapies or neuroprotective strategies is needed desperately. While acyclovir therapy is effective for herpes simplex encephalitis, morbidity and mortality are still prominent in infected patient and additional strategies to treat this disease would improve outcomes in these patients. I have devoted my professional education to the development of research skills. The Mentored Clinical Scientist Development award will be instrumental in the completion of my training in a supportive mentored environment with a multitude of educational resources available to complete my immediate goal of training to be a clinical scientist and completing my long-term goal of becoming an independent clinician scientist.

描述（由申请人提供）：嗜神经病毒是全世界发病率和死亡率的重要原因。由于缺乏对嗜神经病毒致病机制的了解，这些疾病缺乏治疗选择。我们建议研究病毒诱导神经元死亡的机制。基于我们的初步数据，我们将评估c-Jun n -末端激酶（JNK）和转化生长因子(TGF) - β信号在病毒感染原代皮质神经元和小鼠脑炎模型CMS中的作用。一旦这些途径在脑炎呼肠孤病毒模型中被表征，我们也建议在感染西尼罗病毒和单纯疱疹病毒的患者的脑组织中检测这些事件。这些信号通路在病毒诱导的神经元死亡中的具体作用尚不清楚。在这项应用中，我们计划使用多种方法来表征JNK和tgf - β信号在病毒诱导的小鼠神经元凋亡和中枢神经系统损伤中的作用，包括蛋白质分析、病毒操作、病毒突变体、基因阵列分析、实时pcr和激光捕获显微解剖技术。然后将使用呼肠孤病毒感染模型研究中使用的技术对人类脑组织样本进行评估。研究病毒诱导细胞死亡的机制对于开发针对脑和脊髓病毒感染的新靶向治疗和神经保护策略至关重要。目前西尼罗病毒感染没有有效的治疗方法，迫切需要发现新的治疗方法或神经保护策略。虽然阿昔洛韦治疗对单纯疱疹脑炎有效，但感染患者的发病率和死亡率仍然突出，治疗这种疾病的其他策略将改善这些患者的预后。我的专业教育致力于研究技能的发展。导师临床科学家发展奖将有助于我在一个支持性的导师环境中完成培训，这里有大量的教育资源，可以帮助我完成成为一名临床科学家的近期目标，并完成成为一名独立临床科学家的长期目标。