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.

眼内压升高是青光眼发生和发展的主要危险因素 并且是由于小梁网（TM）的损伤导致房水流出受损。我们 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。纤连蛋白胞外结构域A（FN-EDA）是一种已知的损伤相关蛋白， 分子模式（DAMP）和TLR4的内源性配体。FN-EDA是由于组织损伤而产生的 和重塑，导致致病性TM损伤，并且在昏迷性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，其建立终身潜伏感染。HSV-1被以下细胞摄取： 周围神经末梢，支配眼部结构，病毒逆行运输到神经元 在包括三叉神经节（角膜）和睫状神经节（TM）的外周神经节中。进入 神经元潜伏期建立并且潜伏的HSV-1基因组响应于外部应激而重新激活， 包括激活TLR4通路的那些。重要的是，HSV-1的复发性眼部发作是一种常见的眼部疾病。 在美国和世界范围内角膜失明的主要原因，但很少有人知道之间的联系 HSV-1和其他致盲性眼病，如青光眼。以前已经证明HSV-1- 诱导的眼部炎症导致水蛋白和炎性细胞升高以及损伤 TM细胞，其可阻碍房水流出并引起高眼压。HSV-1是一种已知的导致 继发性IOP升高和青光眼，也与青光眼循环危象（一种综合征）相关 以高眼压的反复发作为特征。然而，不知道是否增加了 眼内压和DAMP诱导TM损伤促进潜伏HSV-1的再活化。我们假设 昏迷TM中DAMP的存在重新激活睫状神经节中的HSV-1，导致 复发的HSV-1再活化和炎症导致TM的额外损伤。在此，我们建议 联合收割机将能够支持HSV-1潜伏和再活化的新的体外人神经元细胞系与 HSV-1感染的体内兔眼模型，以确定TM中DAMP的存在是否导致 潜伏的HSV-1的再活化导致对眼部结构的进行性损伤。具体目标1将 确定HSV-1感染是否导致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HSV-1的再激活。总体 该项目的目标是确定HSV-1如何可能有助于与以下相关的发病机制： 青光眼