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: 8649969
• 负责人: William Donegan
• 金额: $ 4.3万
• 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/8649969
• 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

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.

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，有一个 美国的血清阳性为57.7％。眼面表是HSV-1的突出水库 表现为单纯疱疹的病原体（HSL），原发性疱疹性牙龈和口腔内 在硬pa和附着的牙龈上产生的囊泡。 HSL指的是嘴唇和嘴的HSV-1感染， 并且是这些疾病中最常见的。虽然目前的治疗有效地治疗症状 大多数人，HSV-1的抗药性菌株在HSL的免疫功能低下的人群中发展 患者。据报道，HSV-1抗性菌株发生在3.5％-7％的HIV阳性患者中，并且以 造血干细胞接受者的4.1％-10.9％。由于用于治疗感染的大多数药物是 源自Acyclovir并具有相同的作用机理，没有可用的安全有效药物 对待这些人。这提出了开发新型疗法以治疗HSL的迫切需要 通过一种与阿库克罗维尔不同的作用机制。 HSV-1感染发生在口腔粘膜中，该病毒操纵DNA损伤反应 口腔上皮细胞的（DDR）为病毒生产创造最佳环境。 HSV-1激活 共济失调的毛细血管变突变（ATM）传感器激酶，而ATM激活的原因响应于HSV- 1感染未知，生产性感染需要下游信号传导。 ATM激活是 上游事件可能会导致染色质包装和DNA双链破裂的修复 通过同源重组。另外，需要染色质修饰和重组 HSV-1的发病机理。因此，我们假设ATM信号通路的激活是必要的 为了复制HSV-在这里，我们建议通过分析该假设的有效性来评估该假设的有效性 ATM激活病毒基因组的染色质包装状态。我们还将评估重组的方式 病毒基因组受到ATM活性的影响。 这项研究的长期目标是开发与不同的治疗靶标的 Acyclovir的作用机理，可用于治疗HSL的免疫成分个体。之内 拟议项目的范围，我们希望阐明ATM激活的功能 在模拟HSL条件的体外和体内模型系统中生产性HSV-1感染。