Neuroprotection and ERK activation by HSV-2 gene ICP10PK

HSV-2 基因 ICP10PK 的神经保护和 ERK 激活

• 批准号: 7151150
• 负责人: Laure Aurelian
• 金额: $ 35.53万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151150
• 关键词: Acids; Acute; Alzheimer' s Disease; Apoptosis; Apoptotic; BIRC4 gene; Caspase; Caspase Inhibitor; Cell Line; Cells; Cessation of life; Chronic; Cysteine Protease; Data; Development; Engineering; Excision; Failure; Genes; Growth; Hippocampus (Brain); Human Herpesvirus 2; Huntington Disease; In Vitro; Injection of therapeutic agent; Injury; Kainic Acid; Long-Term Potentiation; MEKs; Mediating; Modeling; N-Methylaspartate; Nature; Neurodegenerative Disorders; Neuronal Injury; Neurons; Oxidative Stress; Parkinson Disease; Pathway interactions; Physiologic pulse; Pulse taking; Relative (related person); Site; Slice; Stimulus; Stroke; Synaptic Transmission; Synaptic plasticity; Therapeutic; Therapeutic Intervention; Toxic effect; Virus; base; dentate gyrus; design; in vivo; mutant; neuron apoptosis; neuroprotection; prevent; vector

Death of neurons (apoptosis) occurs in both acute and chronic neurodegenerative diseases such as stroke, Alzheimer's, Parkinson's, and Huntington's diseases and is primarily mediated by activated cysteine proteases (caspases). Cascades of neuronal death emerge gradually, providing a period _vailable for therapeutic intervention. However, the widespread nature of the neuronal injury presents a ',onsiderable challenge to the development of therapeutic strategies. Several strategies were designed to _terrupt the apoptotic cascade but they are limited by problems related to toxicity or the failure to retain neuronal function, likely due to targeting of effectors that function late in the apoptotic cascade. Our )reliminary data indicate that a HSV-2 gene (ICP10PK) prevents apoptosis of CNS neurons in vitro rlduced by various stimuli. We constructed a growth-compromised HSV-2 mutant (ICP10 RR) that etains ICP10PK and anti-apoptotic activity, is not toxic following intrastriatal injection and disseminates to ;onnected sites in the CNS (including hippocampus) upon intranasal delivery. Neuroprotective potential invirus infected cells is due to activation of the Raf/MEK/ERK survival pathway. We propose to evaluate the therapeutic potential of ICP10 PK in acute excitotoxic injury in vivo and define the mechanism of anti-apoptotic activity. The specific aims are: (i) To examine the mechanism of ICP10 PK anti-apoptotic activity in paradigms represented by removal of trophic growth support or oxidative stress, (ii) To engineer vectors that target both both upstream (ICP10 PK) and downstream (XIAP or p35) apoptotic effectors and examine their anti-apopotic activity (relative to ICP10 RR) in organotypic cultures teated with kianic acid (excitotoxic model), (iii) To determine the ability of ICP10 RR and the XlAP/p35 mutants to prevent excitotoxic death in vivo, and (iv) To determine whether ICP10PK expression in the hippocampus maintains synaptic transmission and functional plasticity. The studies will provide significant information required for the development of ICP10PK based therapies for the treatment of acute and chronic neurodegenerative diseases that are associated with apoptosis.

神经元的死亡（细胞凋亡）发生在急性和慢性神经退行性疾病中， 中风、阿尔茨海默氏病、帕金森氏病和亨廷顿氏病，并且主要由活化的 半胱氨酸蛋白酶（半胱天冬酶）。神经元死亡的级联逐渐出现， _可用于治疗干预。然而，神经元损伤的广泛性呈现出一种 “，对治疗策略的发展提出了相当大的挑战。制定了若干战略， _中断凋亡级联，但它们受到与毒性或未能保留 这可能是由于靶向在凋亡级联中后期起作用的效应物。我们 初步研究表明，HSV-2基因（ICP 10 PK）可抑制体外培养的中枢神经系统神经元凋亡 受到各种刺激。我们构建了一个生长受损的HSV-2突变体（ICP 10 RR）， 获得ICP 10 PK和抗凋亡活性，在纹状体内注射后无毒，并扩散至 鼻内递送后CNS（包括海马体）中的连接位点。神经保护电位 病毒感染的细胞的存活是由于Raf/MEK/ERK存活途径的激活。我们建议评估 ICP 10 PK在体内急性兴奋性毒性损伤中的治疗潜力，并确定 抗凋亡活性。具体目的是：（i）研究ICP 10 PK抗凋亡的机制 以去除营养生长支持或氧化应激为代表的范例中的活性，（ii）工程化 靶向上游（ICP 10 PK）和下游（XIAP或p35）凋亡效应物的载体 并在用kianic处理的器官型培养物中检测其抗凋亡活性（相对于ICP 10 RR） （iii）为了确定ICP 10 RR和XIAP/p35突变体防止ICP 10 RR和XIAP/p35突变体的能力， 体内兴奋性毒性死亡，以及（iv）确定海马中ICP 10 PK表达是否 维持突触传递和功能可塑性。这些研究将提供重要信息， 开发用于治疗急性和慢性 与细胞凋亡相关的神经退行性疾病。

项目成果

Multi-targeted neuroprotection by the HSV-2 gene ICP10PK includes robust bystander activity through PI3-K/Akt and/or MEK/ERK-dependent neuronal release of vascular endothelial growth factor and fractalkine.

• DOI: 10.1111/j.1471-4159.2009.06475.x
• 发表时间: 2010-02
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Laing JM;Smith CC;Aurelian L
• 通讯作者: Aurelian L

Binge Drinking: In Search of its Molecular Target via the GABA(A) Receptor.

• DOI: 10.3389/fnins.2011.00123
• 发表时间: 2011
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Yang AR;Liu J;Yi HS;Warnock KT;Wang M;June HL Jr;Puche AC;Elnabawi A;Sieghart W;Aurelian L;June HL Sr
• 通讯作者: June HL Sr

The herpes simplex virus type 2 gene ICP10PK protects from apoptosis caused by nerve growth factor deprivation through inhibition of caspase-3 activation and XIAP up-regulation.

单纯疱疹病毒 2 型基因 ICP10PK 通过抑制 caspase-3 激活和 XIAP 上调来防止神经生长因子剥夺引起的细胞凋亡。

• DOI: 10.1111/j.1471-4159.2007.04745.x
• 发表时间: 2007
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Wales,SamanthaQ;Li,Baiquan;Laing,JenniferM;Aurelian,Laure
• 通讯作者: Aurelian,Laure

Cross talk of signaling and apoptotic cascades in the CNS: target for virus modulation.

中枢神经系统中信号传导和细胞凋亡级联的串扰：病毒调节的目标。

• DOI: 10.2741/1735
• 发表时间: 2005
• 期刊: Frontiers in bioscience : a journal and virtual library
• 作者: Aurelian,Laure