Mechanisms of Apoptosis in Virus-Infected Neurons

描述（由申请方提供）：嗜神经病毒是全世界发病和死亡的重要原因。缺乏对这些疾病的治疗选择是由于缺乏对嗜神经病毒引起疾病的机制的理解。我们建议研究病毒诱导的神经元死亡的机制。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信号传导在病毒感染的原代皮层神经元和小鼠脑炎模型的CMS中的作用。一旦这些途径的特征在于脑炎的呼肠孤病毒模型，我们还建议检查这些事件在人脑组织中获得的患者感染西尼罗河病毒和单纯疱疹病毒。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。在本申请中，我们计划使用多种蛋白质分析、病毒操作、病毒突变体、基因阵列分析、真实的时间PCR和激光捕获显微切割技术来表征JNK和TGF-β信号传导在病毒诱导的小鼠神经元凋亡和CNS损伤中的作用。然后将使用用于在呼肠孤病毒感染模型中研究的技术来评价脑组织的人类样品。研究病毒诱导细胞死亡的机制对于开发新的靶向治疗和脑和脊髓病毒感染的神经保护策略至关重要。目前还没有有效的治疗西尼罗河病毒感染的方法，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病毒性脑炎有效，但感染患者的发病率和死亡率仍然很高，治疗这种疾病的其他策略将改善这些患者的结局。我把我的专业教育奉献给了研究技能的发展。指导临床科学家发展奖将有助于我在一个支持性的指导环境中完成培训，并提供多种教育资源，以完成我培训成为临床科学家的近期目标，并完成我成为独立临床科学家的长期目标。

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.