Targeting the DNA Damage Response for the Treatment of Herpes Simplex Labialis

靶向 DNA 损伤反应治疗单纯性唇疱疹

• 批准号: 8737018
• 负责人: William Donegan
• 金额: $ 4.35万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737018
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acyclovir; Affect; Asses; Ataxia Telangiectasia; Binding; Biological Models; Chromatin; DNA; DNA Damage; DNA Double Strand Break; DNA biosynthesis; Data; Dependence; Development; Drug Targeting; Drug resistance; Drug usage; Environment; Epithelial Cells; Epithelium; Euchromatin; Event; Genetic Recombination; Genome; Gingiva; Goals; HIV Seropositivity; Hard Palate; Hematopoietic stem cells; Herpes Simplex Infections; Herpesvirus 1; Immunocompromised Host; In Vitro; Individual; Infection; Lead; Life Cycle Stages; Lip structure; Lytic Phase; Mission; Oral; Oral cavity; Oral mucous membrane structure; Pain; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phosphorylation; Phosphotransferases; Polymerase; Population; Process; Production; Reporting; Research; Resistance; Role; Scaffolding Protein; Serine; Severities; Signal Pathway; Signal Transduction; Simplexvirus; Site; Structure of trigeminal ganglion; Surface; Symptoms; United States; Vesicle; Viral; Viral Genome; Virus; Work; ataxia telangiectasia mutated protein; base; chromatin modification; homologous recombination; improved; in vitro Model; in vivo Model; inhibitor/antagonist; mouse model; new therapeutic target; novel; novel therapeutics; nucleoside analog; orofacial; particle; pathogen; patient population; programs; public health relevance; repaired; resistant strain; response; sensor; small molecule; therapeutic target; treatment response

DESCRIPTION (provided by applicant): Herpes Simplex Virus 1 (HSV-1) is a ubiquitous pathogen that exists worldwide, and has a seroprevalance of 57.7% in the United States. The oromucosal surface is a prominent reservoir for HSV-1 pathogeneses that manifest as herpes simplex labialis (HSL), primary herpetic gingivostomatis, and intraoral vesicles that arise in the hard palate and attached gingival. HSL refers to HSV-1 infection of the lip and mouth, and is the most common of these maladies. While current treatments are efficacious for treating symptoms in most people, drug resistant strains of HSV-1 have developed in the immunocompromised population of HSL patients. It is reported that HSV-1 resistant strains occur in 3.5%-7% of HIV-positive patients and at a rate of 4.1%-10.9% in recipients of hematopoietic stem cells. Since most of the drugs used to treat infection are derived from acyclovir and have the same mechanism of action, there are no safe and effective drugs available to treat these individuals. This presents a critical need to develop novel therapeutics to treat HSL that function through a mechanism of action distinct from that of acyclovir. HSV-1 infection occurs in the oral mucosa where the virus manipulates the DNA damage response (DDR) of the oral epithelial cell to create an optimal environment for virus production. HSV-1 activates the ataxia telangiectasia mutated (ATM) sensor kinase, and while the cause of ATM activation in response to HSV- 1 infection is unknown, the downstream signaling is required for productive infection. ATM activation is an upstream event that can result in modification of chromatin packaging and repair of DNA double strand breaks by homologous recombination. Additionally, both chromatin modification and recombination are required for the pathogenesis of HSV-1.Therefore, we hypothesize that activation of the ATM signaling pathway is necessary for replication of HSV- Here, we propose to evaluate the validity to this hypothesis by analyzing the impact of ATM activation on the chromatin packaging state of the viral genome. We will also evaluate how recombination of the viral genome is impacted by ATM activity. The long term goal of this research is to develop novel therapeutic targets that differ from the mechanism of action of acyclovir, and can be used to treat immunocompormised individuals with HSL. Within the scope of the proposed project, we expect to elucidate the function(s) of ATM activation -required for productive HSV-1 infection in an in vitro and in vivo model system that mimics HSL conditions.

描述（由申请人提供）：单纯疱疹病毒1（HSV-1）是一种无处不在的病原体，在全球范围内，在美国的血清阳性为57.7％。眼叶表面是表现为HSV-1病原体的突出储层，这些病原体表现为单纯疱疹（HSL），原发性疱疹性gingivostomatis和口腔内囊泡，这些囊泡发生在硬pa而成并附着在牙龈上。 HSL指的是嘴唇和口腔的HSV-1感染，是这些疾病中最常见的。尽管目前的治疗方法可有效治疗大多数人的症状，但HSV-1的HSV-1耐药菌菌株已在HSL患者的免疫功能低下。据报道，HSV-1抗性菌株发生在3.5％-7％的HIV阳性患者中，造血干细胞的受体中以4.1％-10.9％的率发生。由于用于治疗感染的大多数药物都是源自阿昔洛韦的，并且具有相同的作用机理，因此没有可用于治疗这些人的安全有效药物。这提出了开发新型治疗剂来治疗HSL的迫切需要，该HSL通过与阿辛克洛维尔（Acyclovir）不同的作用机制来处理该功能。 HSV-1感染发生在口腔粘膜中，该病毒操纵口腔上皮细胞的DNA损伤反应（DDR），为病毒生产创造了最佳环境。 HSV-1激活了telangiectia突变（ATM）传感器激酶的texia telaxia telangiectia酶，尽管响应HSV-1感染的ATM激活原因尚不清楚，但下游信号传导是生产性感染所必需的。 ATM激活是一个上游事件，可以通过同源重组对染色质包装和DNA双链断裂的修复进行修饰。此外，HSV-1的发病机理需要染色质修饰和重组。因此，我们假设ATM信号传导途径的激活对于HSV的复制是必需的，我们建议通过分析ATM激活对病毒基因组的镀铬蛋白包装状态的影响来评估该假设的有效性。我们还将评估病毒基因组的重组如何受到ATM活性的影响。这项研究的长期目标是开发新型的治疗靶标，这些靶标不同于Acyclovir的作用机理，并可用于治疗HSL的免疫成型个体。在拟议项目的范围内，我们希望在模拟HSL条件的体外和体内模型系统中阐明ATM激活的功能 - 用于生产性HSV -1感染。