Cellular genes and signaling pathways as therapeutic targets for virus-induced CN

描述（由申请人提供）：病毒性脑炎是美国和全世界发病率和死亡率的主要来源。病毒性脑炎已证实的治疗方法仅限于几种病毒，即使存在治疗方法（例如治疗单纯疱疹脑炎的无环鸟苷），残疾和死亡仍然很严重。迫切需要新的和广泛适用的治疗嗜神经病毒感染的策略。通过微阵列分析，我们确定了死亡受体信号通路和过氧化物酶体增殖体激活受体γ (PPAR3)信号通路作为细胞信号通路，在呼肠孤病毒和西尼罗病毒（WNV）感染大脑后的差异基因表达模式中具有显著的代表性。初步数据表明，这些通路调节病毒诱导的神经元细胞死亡和疾病，为病毒性脑炎提供了新的治疗靶点。在拟议的研究中，我们将研究呼肠孤病毒、西尼罗河病毒和单纯疱疹病毒（HSV）感染大脑后这些途径的激活。呼肠孤病毒是病毒性脑炎的“经典”体内实验模型。利用我们最近开发的呼肠孤病毒脑炎体外模型和原代神经元培养体外实验的补充实验，为快速评估病毒诱导的中枢神经系统疾病的治疗靶点提供了一个无与伦比的实验系统。为了增加我们的建议的影响和意义，我们将对临床重要的脑炎病毒，西尼罗河病毒和HSV进行平行实验。为了鉴定可作为病毒性脑炎治疗靶点的新细胞基因和途径，我们将使用呼肠孤病毒、西尼罗河病毒和单纯疱疹病毒的神经毒力毒株和神经减毒毒株对进行一种创造性的微阵列方法。预计在神经毒性和神经减毒病毒株感染后受到差异调节或激活的基因和信号通路将直接参与病毒在脑内的发病机制。因此，我们的实验将确定一组受限的细胞基因和信号通路，这些基因和信号通路将被评估为病毒性脑炎的治疗靶点。已鉴定的基因和信号通路可能适用于单个病毒的治疗靶点。然而，通过鉴定在感染来自不同科的多种病毒后受到差异调节的细胞因子，我们还希望鉴定出具有广谱治疗潜力的细胞靶点，以治疗由各种已知和未知（新出现的）病毒引起的脑炎。我们的研究也有望增加我们对其他以神经元死亡信号的发作或破坏为特征的人类疾病的理解。

DESCRIPTION (provided by applicant): Viral encephalitis is a major source of morbidity and mortality both in the U.S. and throughout the world. Proven treatments for viral encephalitis are limited to only a few viruses and even when treatments exist (e.g. acyclovir for herpes simplex encephalitis) disability and death remain significant. Novel and broadly applicable strategies for the treatment of neurotropic viral infections are desperately needed. Using microarray analysis we identified death receptor signaling and peroxisome proliferator-activated receptor gamma (PPAR3) signaling as cellular signaling pathways that are significantly represented by the pattern of differential gene expression following infection of the brain with reovirus and West Nile virus (WNV), neurotropic viruses from different viral families. Preliminary data suggests that these pathways modulate virus- induced neuronal cell death and disease and provide novel therapeutic targets for viral encephalitis. In the proposed studies we will investigate the activation of these pathways following infection of the brain with reovirus, WNV and herpes simplex virus (HSV). Reovirus represents a "classic" in vivo experimental model of viral encephalitis. Complementary experiments using our recently developed ex vivo model of reovirus encephalitis and in vitro experiments with primary neuronal cultures provide an unmatched experimental system for the rapid evaluation of therapeutic targets for virus-induced CNS disease. To increase the impact and significance of our proposal we will perform parallel experiments with the clinically important encephalitic viruses, WNV and HSV. In order to identify novel cellular genes and pathways that can be used as therapeutic targets for viral encephalitis we will perform an inventive microarray approach using pairs of neurovirulent and neuroattenuated strains of reovirus, WNV and HSV. It is expected that genes and signaling pathways that are differentially regulated or activated following infection with neurovirulent and neuroattenuated viral strains will be directly involved in viral pathogenesis within the brain. Our experiments will thus identify a restricted set cellular genes and signaling pathways that will be evaluated as therapeutic targets for viral encephalitis. Identified genes and signaling pathways may be applicable as therapeutic targets for individual viruses. However, by identifying cellular factors that are differentially regulated following infection with multiple viruses from different families, we also expect to identify cellular targets with broad spectrum therapeutic potential for encephalitis induced by a variety of known and unknown (emerging) viruses. Our studies are also expected to increase our understanding of other human diseases characterized by the onset or disruption of neuronal death signaling. PUBLIC HEALTH RELEVANCE: Virus encephalitis results in significant morbidity and mortality throughout the world. Current treatment strategies which inhibit the replication of individual viruses are inadequate. We propose an alternate strategy to identify and evaluate novel therapeutic targets for virus-induced CNS disease from cellular genes and signaling pathways.