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: 8902108
• 负责人: William Donegan
• 金额: $ 4.39万
• 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/8902108
• 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; Health; 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; 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) 是一种全世界普遍存在的病原体，在美国的血清阳性率为 57.7%。口腔粘膜表面是 HSV-1 病原体的主要储存库，表现为单纯性唇疱疹 (HSL)、原发性疱疹性龈口炎以及硬腭和附着牙龈中出现的口内囊泡。 HSL 是指唇部和口腔的 HSV-1 感染，是这些疾病中最常见的。虽然目前的治疗方法对大多数人的症状有效，但在免疫功能低下的 HSL 患者群体中已经出现了 HSV-1 耐药株。据报道，HIV阳性患者中3.5%-7%存在HSV-1耐药株，造血干细胞接受者中这一比例为4.1%-10.9%。由于大多数用于治疗感染的药物均源自阿昔洛韦并且具有相同的作用机制，因此没有安全有效的药物可用于治疗这些个体。这就迫切需要开发新的疗法来治疗 HSL，其作用机制与阿昔洛韦不同。 HSV-1 感染发生在口腔粘膜中，病毒操纵口腔上皮细胞的 DNA 损伤反应 (DDR)，为病毒产生创造最佳环境。 HSV-1 激活共济失调毛细血管扩张突变 (ATM) 传感器激酶，虽然响应 HSV-1 感染而激活 ATM 的原因尚不清楚，但下游信号传导是有效感染所必需的。 ATM 激活是一个上游事件，可导致染色质包装的修饰以及通过同源重组修复 DNA 双链断裂。此外，HSV-1的发病机制需要染色质修饰和重组。因此，我们假设ATM信号通路的激活对于HSV的复制是必要的。在这里，我们建议通过分析影响来评估该假设的有效性。 ATM 激活对病毒基因组染色质包装状态的影响。我们还将评估 ATM 活动如何影响病毒基因组的重组。这项研究的长期目标是开发不同于阿昔洛韦作用机制的新治疗靶点，可用于治疗患有 HSL 的免疫功能低下个体。在拟议项目的范围内，我们期望阐明在模拟 HSL 条件的体外和体内模型系统中有效 HSV-1 感染所需的 ATM 激活功能。