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

细胞基因和信号通路作为病毒诱导 CN 的治疗靶点

• 批准号: 8712570
• 负责人: Kenneth L. Tyler
• 金额: $ 34.08万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712570
• 关键词: Acyclovir; Apoptosis; Apoptotic; Brain; Brain Injuries; Caspase; Caspase Inhibitor; Cell Death; Central Nervous System Diseases; Cessation of life; Clinical; Data; Disease; Encephalitis; Encephalitis Viruses; Evaluation; Experimental Models; Family; Genes; Genetic Transcription; Genetically Modified Animals; Goals; HIV; Herpes encephalitis; Hospitalization; In Vitro; Individual; Infection; Inflammatory Response; Microarray Analysis; Mitogen-Activated Protein Kinases; Modeling; Morbidity - disease rate; Mus; Neuroglia; Neurons; Nuclear Receptors; PPAR gamma; Pathway Analysis; Pathway interactions; Pattern; Peptide Hydrolases; Peroxisome Proliferator-Activated Receptors; Proteins; Receptor Signaling; Reoviridae Infections; Reovirus; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Pathway Gene; Simplexvirus; Source; System; Testing; Therapeutic; Tissue-Specific Gene Expression; Transcriptional Regulation; Viral; Viral Encephalitis; Viral Pathogenesis; Virus; Virus Diseases; West Nile virus; activating transcription factor; caspase-3; caspase-8; cell growth regulation; cellular targeting; clinically relevant; disability; human disease; in vivo; in vivo Model; inhibitor/antagonist; mortality; neuron loss; neurotropic; neurotropic virus; new therapeutic target; novel; receptor; research study; therapeutic target; transcription factor; treatment strategy

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.

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。经证实的病毒性脑炎治疗方法仅限于少数病毒，即使存在治疗方法（例如用于治疗单纯疱疹脑炎的阿昔洛韦），残疾和死亡仍然很严重。迫切需要治疗嗜神经病毒感染的新颖且广泛适用的策略。 使用微阵列分析，我们确定了死亡受体信号传导和过氧化物酶体增殖物激活受体γ（PPAR3）信号传导作为细胞信号传导途径，这些信号传导途径以脑部感染呼肠孤病毒和西尼罗河病毒（WNV）、神经营养性病毒后差异基因表达的模式为显着代表。来自不同病毒家族的病毒。初步数据表明，这些途径调节病毒诱导的神经元细胞死亡和疾病，并为病毒性脑炎提供新的治疗靶点。在拟议的研究中，我们将研究大脑感染呼肠孤病毒、西尼罗河病毒和单纯疱疹病毒（HSV）后这些通路的激活情况。呼肠孤病毒代表了病毒性脑炎的“经典”体内实验模型。使用我们最近开发的呼肠孤病毒脑炎离体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引起的中枢神经系统疾病的治疗靶点提供了无与伦比的实验系统。为了增加我们提案的影响和意义，我们将对临床上重要的脑炎病毒 WNV 和 HSV 进行平行实验。 为了鉴定可用作病毒性脑炎治疗靶点的新细胞基因和途径，我们将使用成对的呼肠孤病毒、WNV 和 HSV 的神经强毒株和神经减毒株进行创造性的微阵列方法。预计神经毒力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传导途径将直接参与大脑内的病毒发病机制。因此，我们的实验将确定一组有限的细胞基因和信号通路，将其作为病毒性脑炎的治疗靶点进行评估。已确定的基因和信号传导途径可用作单个病毒的治疗靶点。然而，通过识别不同家族的多种病毒感染后受到差异调节的细胞因子，我们还期望识别出对多种已知和未知（新兴）病毒引起的脑炎具有广谱治疗潜力的细胞靶点。我们的研究还有望增加我们对以神经元死亡信号发生或破坏为特征的其他人类疾病的理解。

项目成果

PML therapy: "It's Déjà vu all over again".

PML 疗法：“似曾相识的感觉又来了”。

• 发表时间: 2013-08
• 影响因子: 3.2
• 作者: Tyler; Kenneth L
• 通讯作者: Kenneth L