HSV-1 reactivation and glaucomatous trabecular meshwork damage

HSV-1 重新激活和青光眼小梁网损伤

• 批准号: 10592565
• 负责人: Colleen Mary McDowell
• 金额: $ 22.99万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592565
• 关键词: Address; Aqueous Humor; Blindness; Cell Culture Techniques; Cell Line; Cell model; Cells; Cornea; Development; Disease; Drainage procedure; Eye; Eye Development; Eye diseases; Family; Fibronectins; Ganglia; Genome; Glaucoma; Goals; Herpes Simplex Infections; Herpesvirus 1; Human; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Knowledge; Ligands; Modeling; Molecular; Mus; Nerve; Neurons; Ocular Hypertension; Open-Angle Glaucoma; Optic Nerve; Oryctolagus cuniculus; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Peripheral; Peripheral Nerves; Phenotype; Physiologic Intraocular Pressure; Primary Infection; Production; Proteins; Recurrence; Resistance; Risk; Risk Factors; Role; Signal Transduction; Structure; Structure of ciliary ganglion; Structure of trigeminal ganglion; Syndrome; TLR4 gene; Testing; Tissues; Trabecular meshwork structure; Transforming Growth Factor beta; Viral Genes; Virus; Virus Activation; anterograde transport; aqueous; in vivo; latent infection; nerve damage; novel; optic nerve disorder; pressure; prevent; reactivation from latency; receptor; response; retrograde transport; stressor

Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of glaucoma and is due to damage to the trabecular meshwork (TM) leading to impaired aqueous humor outflow. We have shown that toll-like receptor 4 (TLR4) is an important receptor involved in the development of ocular hypertension and TM damage. Fibronectin extra domain A (FN-EDA) is a known damage associated molecular pattern (DAMP) and endogenous ligand of TLR4. FN-EDA is produced because of tissue damage and remodeling, leads to pathogenic TM damage, and is increased in the glaucomatous TM. Herpes simplex virus 1 (HSV-1) is a ubiquitous human virus that establishes a lifelong latent infection. HSV- 1 is taken up by peripheral nerve termini that innervate ocular structures, and the virus is retrograde transported to neurons in the peripheral ganglia including the trigeminal ganglia (cornea) and ciliary ganglia (TM). After entering neurons latency is established and latent HSV-1 genomes reactivate in response to external stressors, including those that activate the TLR4 pathway. Importantly, recurrent ocular episodes of HSV-1 are a leading cause of corneal blindness in the US and worldwide, yet little is known about the connection between HSV-1 and other blinding eye diseases, such as glaucoma. It has been previously shown that HSV-1- induced ocular inflammation leads to elevated aqueous proteins and inflammatory cells as well as damage to TM cells, which can impede aqueous outflow and cause ocular hypertension. HSV-1 is a known cause of secondary elevated IOP and glaucoma and is also associated with Glaucomatocyclic Crisis, a syndrome characterized by recurrent attacks of ocular hypertension. However, it is unknown whether increased intraocular pressure and DAMP-induced TM damage facilitate reactivation of latent HSV-1. We hypothesize that the presence of DAMPs in the glaucomatous TM reactivate HSV-1 in the ciliary ganglia, leading to recurrent HSV-1 reactivation and inflammation resulting in additional damage to the TM. Here we propose to combine a novel in vitro human neuronal cell line capable of supporting HSV-1 latency and reactivation with an in vivo rabbit ocular model of HSV-1 infection to determine if the presence of DAMPs in the TM result in reactivation of latent HSV-1 leading to progressive damage to ocular structures. Specific aims 1 will determine whether HSV-1 infection causes TM damage and DAMP production, and Specific aim 2 will determine whether DAMP activated TLR4 signaling leads to HSV-1 reactivation in neurons. The overarching goal of this project is to determine how HSV-1 might contribute to the pathogenesis associated with glaucoma.

眼内压（IOP）升高是青光眼发生和进展的主要危险因素 这是由于小梁网 (TM) 受损导致房水流出受损。我们 研究表明，Toll 样受体 4 (TLR4) 是参与眼部发育的重要受体。 高血压和TM损伤。纤连蛋白额外结构域 A (FN-EDA) 是一种已知的相关损伤 TLR4 的分子模式 (DAMP) 和内源性配体。 FN-EDA因组织损伤而产生 和重塑，导致致病性 TM 损伤，并且在青光眼 TM 中增加。单纯疱疹 病毒 1 (HSV-1) 是一种普遍存在的人类病毒，可形成终生潜伏感染。 HSV-1 被吸收 支配眼部结构的周围神经末梢，病毒逆行转运至神经元 周围神经节包括三叉神经节（角膜）和睫状神经节（TM）。进入后 神经元潜伏期建立，潜伏的 HSV-1 基因组响应外部压力源重新激活， 包括那些激活 TLR4 通路的物质。重要的是，HSV-1 的反复眼部发作是 在美国和世界范围内，角膜失明的主要原因，但人们对两者之间的联系知之甚少 HSV-1 和其他致盲眼病，例如青光眼。此前已有研究表明，HSV-1- 诱发的眼部炎症导致水蛋白和炎症细胞升高以及损伤 TM 细胞，这会阻碍房水流出并导致高眼压。 HSV-1 是导致 继发性眼压升高和青光眼，也与青光眼循环危象（一种综合征）相关 其特点是高眼压症反复发作。但是否增加尚不得而知 眼内压和 DAMP 诱导的 TM 损伤促进潜伏 HSV-1 的重新激活。我们假设 青光眼 TM 中 DAMP 的存在重新激活了睫状神经节中的 HSV-1，从而导致 复发性 HSV-1 重新激活和炎症导致 TM 受到额外损伤。在此我们建议 将能够支持 HSV-1 潜伏和重新激活的新型体外人类神经细胞系与 HSV-1 感染的体内兔眼模型，以确定 TM 中 DAMP 的存在是否会导致 潜伏的 HSV-1 重新激活，导致眼部结构进行性损伤。具体目标 1 将 确定 HSV-1 感染是否会导致 TM 损伤和 DAMP 产生，具体目标 2 将 确定 DAMP 激活的 TLR4 信号传导是否导致神经元中的 HSV-1 重新激活。首要的 该项目的目标是确定 HSV-1 如何促进与以下疾病相关的发病机制： 青光眼。