Neuroprotection and ERK activation by HSV-2 gene ICP10PK
HSV-2 基因 ICP10PK 的神经保护和 ERK 激活
基本信息
- 批准号:6561675
- 负责人:
- 金额:$ 33.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-12-01 至 2007-11-30
- 项目状态:已结题
- 来源:
- 关键词:PC12 cells apoptosis biotechnology cell growth regulation combination therapy enzyme induction /repression enzyme therapy gene expression gene induction /repression gene therapy herpes simplex virus 2 hippocampus laboratory mouse long term potentiation mitogen activated protein kinase neural degeneration neural plasticity neuroprotectants nonhuman therapy evaluation organ culture posttranslational modifications ribonucleotide reductase terminal nick end labeling transcription factor transfection /expression vector western blottings
项目摘要
DESCRIPTION (provided by applicant): 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 available for therapeutic intervention. However, the widespread nature of the neuronal injury presents a considerable challenge to the development of therapeutic strategies. Several strategies were designed to interrupt 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 preliminary data indicate that a HSV-2 gene (ICP10PK) prevents apoptosis of CNS neurons in vitro produced by various stimuli. We constructed a growth-compromised HSV-2 mutant (ICP10 RR) that retains ICP10PK and anti-apoptotic activity, is not toxic following intrastriatal injection and disseminates to connected sites in the CNS (including hippocampus) upon intranasal delivery. Neuroprotective potential in virus-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 upstream (ICP10 PK) and downstream (XIAP or p35) apoptotic effectors and examine their anti-apoptotic activity (relative to ICP10 RR) in organotypic cultures treated 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.
描述(申请人提供):神经元死亡(凋亡)发生在急性和慢性神经变性疾病如中风、阿尔茨海默病、帕金森病和亨廷顿病中,并且主要由活化的半胱氨酸蛋白酶(半胱天冬酶)介导。神经元死亡的级联反应逐渐出现,为治疗干预提供了一段时间。然而,神经元损伤的广泛性对治疗策略的发展提出了相当大的挑战。设计了几种策略来中断凋亡级联,但它们受到与毒性或未能保留神经元功能相关的问题的限制,这可能是由于靶向在凋亡级联后期起作用的效应物。我们的初步数据表明,HSV-2基因(ICP 10 PK)防止由各种刺激产生的CNS神经元在体外的凋亡。我们构建了一种生长受损的HSV-2突变体(ICP 10 RR),其保留了ICP 10 PK和抗凋亡活性,在纹状体内注射后没有毒性,并在鼻内递送后传播到CNS(包括海马)中的连接部位。病毒感染细胞中的神经保护潜力是由于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,并确定抗凋亡活性的机制。具体目标是:(i)在以去除营养生长支持或氧化应激为代表的范例中检查ICP 10 PK抗凋亡活性的机制,(ICP 10 PK)和下游(XIAP或p35)凋亡效应物,并检查它们的抗凋亡活性(相对于ICP 10 RR)在用kianic酸处理的器官型培养物中(iii)为了确定ICP 10 RR和X1 AP/p35突变体在体内预防兴奋性毒性死亡的能力,以及(iv)确定海马中的ICP 10 PK表达是否维持突触传递和功能可塑性。这些研究将为开发用于治疗与细胞凋亡相关的急性和慢性神经退行性疾病的基于ICP 10 PK的疗法提供重要信息。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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{{ truncateString('Laure Aurelian', 18)}}的其他基金
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过量饮酒与 GABA Alpha 2 调节的 TLR4 表达相关
- 批准号:
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- 资助金额:
$ 33.29万 - 项目类别:
Excessive Alcohol Drinking Associated with GABA Alpha 2-Regulated TLR4 Expression
过量饮酒与 GABA Alpha 2 调节的 TLR4 表达相关
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- 资助金额:
$ 33.29万 - 项目类别:
Excessive Alcohol Drinking Associated with GABA Alpha 2-Regulated TLR4 Expression
过量饮酒与 GABA Alpha 2 调节的 TLR4 表达相关
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Apoptosis of skin melanoma by the new Hsp H11
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新热休克蛋白H11导致皮肤黑色素瘤细胞凋亡
- 批准号:
7643232 - 财政年份:2007
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Apoptosis of skin melanoma by the new Hsp H11
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$ 33.29万 - 项目类别:
Neuroprotection and ERK activation by HSV-2 gene ICP10PK
HSV-2 基因 ICP10PK 的神经保护和 ERK 激活
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$ 33.29万 - 项目类别:
Neuroprotection and ERK activation by HSV-2 gene ICP10PK
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7151150 - 财政年份:2002
- 资助金额:
$ 33.29万 - 项目类别:
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