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.

升高的眼压（IOP）是青光眼发展和发展的主要危险因素 并且是由于对小梁网（TM）的损害，导致水性幽默流出受损。我们 已经表明，Toll样受体4（TLR4）是参与眼的发展的重要受体 高血压和TM损伤。纤连蛋白额外的结构域A（FN-EDA）是已知的损害 TLR4的分子模式（湿）和内源配体。由于组织损伤而产生FN-EDA 并重塑，导致致病性TM损伤，并在青光眼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，可建立终生潜在感染。 HSV- 1由 支配眼结构的周围神经末端，并将病毒逆行转运至神经元 在包括三叉神经节（角膜）和睫毛神经节（TM）的外围神经节中。进入后 建立神经元潜伏期，潜在的HSV-1基因组反应外部压力源， 包括激活TLR4途径的那些。重要的是，HSV-1的复发性眼发作是一个 美国和全球角膜失明的主要原因，但对之间的联系知之甚少 HSV-1和其他盲目的眼部疾病，例如青光眼。以前已经证明了HSV-1- 引起的眼部炎症会导致水性蛋白质和炎症细胞升高，并损害 对TM细胞，这会阻碍水流流出并引起眼部高血压。 HSV-1是已知的原因 二级升高的IOP和青光眼，也与青光眼危机（综合征）有关 以眼高血压的复发性攻击为特征。但是，未知是否增加 眼内压力和潮湿诱导的TM损伤有助于潜在的HSV-1重新激活。我们假设 胶状神经节中的青光眼TM中湿的存在对HSV-1的存在，导致 复发性HSV-1重新激活和炎症会对TM造成额外的损害。在这里我们建议 结合一种新型体外人类神经元细胞系，能够支持HSV-1潜伏期和重新激活 HSV-1感染的体内兔眼模型，以确定TM中的潮湿是否是否导致 潜在的HSV-1重新激活导致眼睛结构逐渐损害。具体目标1将 确定HSV-1感染是否会导致TM损伤和潮湿的产生，并且特定的AIM 2将会 确定潮湿激活的TLR4信号传导是否导致神经元中的HSV-1重新激活。总体 该项目的目标是确定HSV-1如何促进与之相关的发病机理 青光眼。