Ocular HSV-Latency, Reactivation, and Recurrence

眼部 HSV 潜伏期、再激活和复发

• 批准号: 8091265
• 负责人: JAMES M HILL
• 金额: $ 42.08万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091265
• 关键词: Affect; Alleles; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Biological; Biological Products; Blepharitis; Blindness; Characteristics; Chemical Agents; Chromatin; Combination Drug Therapy; Combined Modality Therapy; Complex; Conjunctivitis; Developed Countries; Disease; Encephalitis; Epigenetic Process; Epithelial; Exhibits; Eye; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genome; Goals; Health; Herpesvirus 1; Herpetic Keratitis; Histones; Human; Infection; Investigation; Keratitis; Knock-in Mouse; Lesion; Molecular; Mouse Strains; Mus; Neurons; Pathogenesis; Patients; Peptides; Peripheral; Phenotype; Predisposition; Recurrence; Recurrent disease; Regulation; Research; Resistance; Risk Factors; Role; Severities; Simplexvirus; Site; Stimulus; Structure of trigeminal ganglion; Targeted Research; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Translational Research; United States; Viral; Viral Physiology; Virus; Virus Diseases; Virus Latency; Vision; Vision research; base; chromatin remodeling; corneal epithelium; corneal scar; experience; genetic risk factor; genital herpes; herpes 2; mimetics; mouse model; oxidative damage; patient population; public health relevance; reactivation from latency; receptor; relating to nervous system

DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) is the leading cause of infectious blindness in the industrialized nations. In the USA, 300,000 cases are treated yearly. Ocular HSV causes a self-limiting epithelial keratitis, blepharitis, con- junctivitis, stromal keratitis, and the most damaging disease, necrotizing herpetic stromal keratitis (HSK). HSK is the most difficult to manage; about half of the patients do not respond to combination chemotherapy and will have significant loss of vision or blindness. HSV is a neurotrophic virus characterized by its ability to establish lifelong latency in neurons and to reactivate at peripheral sites, causing recurrent disease. The ocular recur- rences cause significant corneal scarring, leading to HSK. Our proposal will examine the relationship between low and high HSV-1 phenotypic reactivators in a mouse model highly susceptible to ocular pathogenesis. The e4 allele of Apolipoprotein E (ApoE) is a risk factor for ocular herpes. We will demonstrate that different phenotypes (strains) of HSV have different ocular pathogenesis in e4 knock-in mice, a transgenic mouse strain created by insertion of the human ApoE gene into a trans- genic mouse from which the mouse ApoE gene was removed. We will evaluate two ApoE mimetic receptor- based peptides that separately exhibit anti-viral and anti-herpetic activity in a combination therapy to treat the severe ocular pathogenesis resulting from HSV-1 infection in e4 mice. We hypothesize that our investigation using the two ApoE peptides will document a reduction in ocular pathogenesis and oxidative damage in neurons and epigenetic control that is affected by this therapy. To this end, we plan to follow these Specific Aims: Specific Aim 1: To test the hypothesis that significant differences in ocular pathogenesis will occur in e4 mice when infected with high and low phenotypic reactivating strains of HSV-1. Specific Aim 2: To test the hypothesis that more pathogenesis will occur when ApoE e4 mice latently infected with the high phenotypic reactivator are induced to reactivate than in those latently infected with the low phenotypic reactivator. Specific Aim 3: To test the hypothesis that therapy with two unique ApoE peptides will successfully inhibit the induction of HSV-1 reactivation of the high phenotypic reactivator in ApoE e4 mice. These studies, if successful, will demonstrate 1) the role of contrasting HSV-1 phenotypic strains in ocular herpes, 2) the susceptibility and increased pathogenesis of the e4 allele carrier using mice latent with a high phenotypic reactivator and given an HSV-1 induction stimulus, and 3) that two ApoE peptides can inhibit HSV- 1 reactivation and ocular pathogenesis, even in highly susceptible e4 mice that are given an HSV-1 inducer. These pharmacological studies will offer the possibility of a new combination therapy for patients with ocular herpes and possibly for other HSV diseases such as encephalitis and genital herpes. These studies involving translational research, epigenetics, and ocular pathogenesis are in accordance with the research goals of the December 2006 National Plan for Eye and Vision Research. PUBLIC HEALTH RELEVANCE: Herpes Simplex Virus (HSV) is the leading cause of infectious, non-traumatic blindness in all industrialized nations, with over 300,000 cases treated in the United States per year. While therapies are available, some patients remain strongly resistant to current treatments, thus our research targets a specific human gene, the e4 allele of apolipoprotein E (ApoE), which has been implicated in the pathogenesis of ocular HSV- 1. The use of two receptor-based ApoE mimetic peptides that exhibit potent anti-viral and anti-inflammatory activity, and which act to suppress this gene, holds great promise as a new therapy for ocular and other HSV-related diseases.

描述（由申请人提供）：单纯疱疹病毒（HSV）是工业化国家传染病的主要原因。在美国，每年对30万例案件进行治疗。眼HSV会引起自限制的上皮性角膜炎，睑缘炎，连锁性炎，基质角膜炎和最具破坏性的疾病，坏死性疱疹性基质角膜炎（HSK）。 HSK是最难管理的；大约一半的患者对化疗没有反应，并且视力或失明会大大丧失。 HSV是一种神经营养性病毒，其特征在于其在神经元中建立终生潜伏期并在外周部位重新激活的能力，从而导致复发性疾病。眼部相互作用会引起明显的角膜疤痕，导致HSK。我们的建议将检查在高度容易受眼发病机理的小鼠模型中，低HSV-1表型重新激活剂之间的关系。载脂蛋白E（APOE）的E4等位基因是眼疱疹的危险因素。我们将证明，HSV的不同表型（菌株）在E4敲入小鼠中具有不同的眼部发病机理，这是一种通过将人ApoE基因插入到转基因小鼠中而产生的转基因小鼠菌株，从中取出了小鼠APOE基因。我们将评估两种APOE模拟受体基于抗病毒和抗疱疹活性在联合疗法中，以治疗E4小鼠中HSV-1感染引起的严重眼科发病机制。我们假设使用两种APOE肽进行的研究将记录在神经元和受此疗法影响的神经元和表观遗传控制中的眼部发病机理和氧化损伤的降低。为此，我们计划遵循以下特定目标：具体目的1：测试以下假设：当感染高和低表型的HSV-1菌株时，E4小鼠中眼发病的显着差异将发生。具体目的2：检验以下假设：当ApoE E4小鼠被高表型重新激活剂的apoE E4小鼠被诱导的重新激活时，将发生更多的发病机理。特定目的3：测试以下假设：使用两种独特的APOE肽治疗将成功抑制APOE E4小鼠中高表型反抗器的HSV-1重新激活的诱导。这些研究（如果成功）将证明1）在眼疱疹中对比鲜明的HSV-1表型菌株的作用，2）使用具有高表型反应活化剂的小鼠的E4等位基因载体的敏感性和增加的E4等位基因载体的发病机理，并给出了HSV-1诱导刺激，以及两个APOES的抑制作用，即使是Sustible octiber in partive and partive and partive and partive and partive and partiv-1 partiv-hsv-1反应型，迫切型HSV-1反应型，并且具有强化的HSV-1反应型，并且具有强化的HSV-1反应型，并且具有迫切的HSV-1反应型，并且具有强化性的HSV-1反应型。给出了HSV-1诱导剂的小鼠。这些药理学研究将为眼疱疹患者以及其他HSV疾病（例如脑炎和生殖器疱疹）提供新的联合疗法。这些涉及转化研究，表观遗传学和眼部发病机理的研究符合2006年12月的《国家眼睛和视力研究计划》的研究目标。公共卫生相关性：单纯疱疹病毒（HSV）是所有工业化国家传染性，非创伤失明的主要原因，每年在美国进行30万例病例。 While therapies are available, some patients remain strongly resistant to current treatments, thus our research targets a specific human gene, the e4 allele of apolipoprotein E (ApoE), which has been implicated in the pathogenesis of ocular HSV- 1. The use of two receptor-based ApoE mimetic peptides that exhibit potent anti-viral and anti-inflammatory activity, and which act to suppress this gene, holds great promise as a new眼部和其他与HSV相关疾病的治疗。