EXPRESSION OF NERVE GROWTH-FACTOR INVIVO FROM A DEFECTIVE HERPES-SIMPLEX VIRUS-1 VECTOR PREVENTS EFFECTS OF AXOTOMY ON SYMPATHETIC-GANGLIA
EXPRESSION OF NERVE GROWTH-FACTOR INVIVO FROM A DEFECTIVE HERPES-SIMPLEX VIRUS-1 VECTOR PREVENTS EFFECTS OF AXOTOMY ON SYMPATHETIC-GANGLIA
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DOI：
10.1073/pnas.89.5.1636
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发表时间：
1992-03-01
影响因子：
11.1
通讯作者：
KESSLER, JA
中科院分区：
文献类型：
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作者：
FEDEROFF, HJ;GESCHWIND, MD;KESSLER, JA
成年大鼠颈上神经节（SCG）交感神经元依赖靶源性神经生长因子（NGF）维持酪氨酸羟化酶（TH）水平和去甲肾上腺素能神经递质系统。截肛SCG导致NGF剥夺，导致TH活性下降；持续局部应用NGF可以防止TH活性的下降。我们现在报道，将表达NGF的有缺陷的单纯疱疹病毒1载体（pHSVngf）注射到SCG中，可以防止肛切术后TH活性的下降。将表达大肠杆菌-半乳糖苷酶的pHSVngf病毒或pNFlac病毒分别注射于成年大鼠SCG。从phsvngf感染的SCG中提取的RNA分析表明，NGF基因被有效地转录和加工。此外，注射pHSVngf 4天后，动物对注射病毒的SCG进行了肛门切开术。再过10天，处死动物，检测注射后的对侧对照神经节和切开的对侧对照神经节的TH活性。注射pNFlac病毒的SCG切开后，与对照神经节相比，TH活性下降50% （P = 0.02）。相比之下，注射pHSVngf病毒的SCG在肛切开术后未显示TH活性下降；相反，这些神经节的TH水平比对照神经节高18%。这些数据表明，单纯疱疹病毒1型载体可用于改变体内神经元生理；具体来说，神经细胞表达一种通常不产生的关键基因产物具有基因治疗的潜在应用。
Sympathetic neurons in the superior cervical ganglion (SCG) of adult rats depend on target-derived nerve growth factor (NGF) for maintenance of tyrosine hydroxylase (TH) levels and the noradrenergic neurotransmitter system. Axotomy of a SCG results in NGF deprivation, causing a decline in TH activity; continuous local application of NGF can prevent this decline in TH activity. We now report that injection of a defective herpes simplex virus 1 vector that expresses NGF (pHSVngf) into a SCG can prevent the decline in TH activity that follows axotomy. SCG of adult rats were injected with either pHSVngf virus or pNFlac virus, which expresses Escherichia coli beta-galactosidase. Analysis of RNA from pHSVngf-infected SCG indicated that the NGF gene was efficiently transcribed and processed. Furthermore, 4 days after pHSVngf injection animals underwent axotomy of the virus-injected SCG. After another 10 days, animals were sacrificed and both the injected-axotomized and contralateral control ganglia were assayed for TH activity. Axotomy of SCG injected with pNFlac virus produced a 50% decline in TH activity relative to control ganglia (P = 0.02). In contrast, SCG injected with pHSVngf virus did not show a decline in TH activity following axotomy; instead, these ganglia manifested an 18% increase in TH levels relative to control ganglia. These data demonstrate that herpes simplex virus 1 vectors can be used to modify neuronal physiology in vivo; specifically, expression of a critical gene product by neural cells that do not normally produce it has potential applications for gene therapy.