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Corneal HSV-1: LAT Blocks Apoptosis in Rabbit TG

角膜 HSV-1：LAT 阻断兔 TG 细胞凋亡

基本信息

批准号：
6326521
负责人：
STEVEN L WECHSLER
金额：
$ 42.44万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-06-01 至 2002-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6326521
关键词：
PC12 cells apoptosis cornea eye infections gene expression genetic mapping glia herpes simplex virus 1 laboratory rabbit latent virus infection neurons polymerase chain reaction regulatory gene relapse /recurrence trigeminal nerve virus infection mechanism

项目摘要

DESCRIPTION (provided by applicant): Recurrent herpes simplex virus type 1 (HSV-l) infection is a major cause of viral induced blindness. Understanding the molecular mechanisms of the HSV-l latency-reactivation cycle, should lead to development of a means for reducing the incidence of HSV-I induced blindness. LAT, the only HSV-l gene abundantly transcribed during latency is essential for efficient spontaneous reactivation. However, the underlying mechanism remains unknown. We recently showed that plasmids expressing LAT block apoptosis in tissue culture. Also, in trigeminal ganglia (TG) of rabbits ocularly infected with a LAT- mutant extensive apoptosis occurs on day 7 post infection (during transition from lytic to latent infection). In contrast, little apoptosis occurs in TG of rabbits ocularly infected with LAT+ virus (wt or marker rescued). This LAT anti-apoptosis function could enhance spontaneous reactivation by promoting neuronal survival following acute infection, thereby making a larger pool of latently infected neurons available for reactivation. The main hypothesis to be tested in this proposal is: LAT enhances spontaneous reactivation by blocking apoptosis. The Specific Aims are: 1. Fine map the region of LAT responsible for blocking apoptosis in rabbit TG. Our existing library of LAT mutants will be analyzed for anti-apoptosis activity in vivo in rabbit TG. Additional mutants expressing progressively smaller LAT regions will be constructed and analyzed for anti-apoptosis activity and spontaneous reactivation. If LAT's anti-apoptosis function co-maps with LAT's spontaneous reactivation function, it would strongly support the hypothesis that LAT enhances reactivation by blocking apoptosis. 2. Determine if LAT's reactivation function can be replaced by alternative anti-apoptosis genes. Various anti-apoptosis genes under control of the LAT promoter will be individually inserted into a LAT mutant that does not block apoptosis during acute infection of rabbit TG and that has low levels of spontaneous reactivation. If blocking apoptosis and enhancing spontaneous reactivation are restored to wild type levels, it would confirm that LAT enhances reactivation by blocking apoptosis.

描述（由申请人提供）：复发性单纯疱疹病毒1型