Mechanisms of Apoptosis in Virus-Infected Neurons

病毒感染神经元的凋亡机制

• 批准号: 7807965
• 负责人: John David Beckham
• 金额: $ 14.05万
• 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/7807965
• 关键词: Acyclovir; Apoptosis; Brain; Cell Death; Cessation of life; Clinical; Data; Development; Disease; Encephalitis; Environment; Event; Genes; Goals; Herpes encephalitis; Human; Infection; Mentored Clinical Scientist Development Award (K08); Mentors; Methods; Modeling; Morbidity - disease rate; Mus; Neurons; Outcome; Pathway interactions; Patients; Professional Education; Protein Analysis; Reovirus; Resources; Role; Sampling; Scientist; Signal Pathway; Signal Transduction; Simplexvirus; Spinal Cord; Techniques; Therapeutic; Time; Training; Transforming Growth Factor beta; Viral; Virus; Virus Diseases; West Nile virus; base; brain tissue; central nervous system injury; effective therapy; improved; laser capture microdissection; mortality; mutant; neuron apoptosis; neurotropic virus; research and development; skills; stress-activated protein kinase 1

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）：神经性病毒是全世界发病率和死亡率的重要原因。这些疾病缺乏治疗选择是由于对神经性病毒引起疾病的机制的理解很少。我们建议研究导致病毒诱发神经元死亡的机制。根据我们的初步数据，我们将评估C-Jun N末端激酶（JNK）和转化生长因子（TGF）-BetA信号在原发性皮质神经元病毒感染过程中的作用以及小鼠脑膜炎模型的CMS的作用。一旦这些途径在脑炎的葡萄病毒模型中进行了表征，我们还建议检查从感染了西尼罗河病毒和单纯疱疹病毒的患者获得的人类脑组织中的这些事件。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。在此应用中，我们计划使用多种蛋白质分析，病毒操纵，病毒式突变体，基因阵列分析，实时PCR和激光匹配的微射击技术来表征JNK和TGF-β信号在病毒诱导的神经元凋亡中的作用和CNS损伤。然后，将使用用于研究中用于研究的技术的技术来评估脑组织的人类样品。负责病毒诱导细胞死亡的机制的研究对于开发针对大脑和脊髓病毒感染的新靶向疗法和神经保护策略至关重要。迫切需要针对西尼罗河病毒感染以及新疗法或神经保护策略发现的有效疗法。虽然阿昔洛韦疗法对单纯疱疹脑炎有效，但在感染患者中仍然显着发病和死亡率，并且治疗这种疾病的其他策略将改善这些患者的预后。我将专业教育致力于发展研究技能。指导的临床科学家发展奖将在我在支持性指导环境中的培训中发挥作用，并拥有大量的教育资源，可以完成我的近期培训目标，即成为临床科学家，并完成我成为独立临床医生的长期目标。