Role of insulin-like growth factor binding proteins in the pathogenesis of herpes stromal keratitis.

胰岛素样生长因子结合蛋白在疱疹基质角膜炎发病机制中的作用。

基本信息

批准号：
10056782
负责人：
Susmit Suvas
金额：
$ 37.74万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10056782
关键词：
Ablation Adrenal Cortex Hormones Antiviral Agents Biological Assay Biological Availability Blindness Blocking Antibodies Blood Circulation Blood Vessels Cataract Cell Aging Cell surface Chronic Clinical Confocal Microscopy Cornea Corneal Stroma Corneal edema Development Disease Enzyme-Linked Immunosorbent Assay Epithelial Cells Event Eye Infections Glaucoma Goals Herpesvirus 1 Human Hypoxia Immunomodulators Impaired wound healing Infection Inflammation Inflammatory Insulin-Like Growth Factor Binding Protein 3 Insulin-Like Growth Factor I Insulin-Like Growth Factor II Insulin-Like Growth-Factor-Binding Proteins Insulin-Like-Growth Factor I Receptor Keratitis Knock-out Knockout Mice Knowledge Lesion Leukocytes Measures Membrane Molecular Mus Myelogenous Myeloid Cells Oral Outcome Outcome Measure Pathogenesis Phosphorylation Physiologic Intraocular Pressure Plasmids Predisposition Protein Array Proteins Publishing Receptor Signaling Recombinant Insulin-Like Growth Factor Recurrence Reporting Risk Role Sampling Severities Somatomedins Stains Steroids Tamoxifen Testing Time Topical application Tyrosine Kinase Inhibitor Tyrosine Phosphorylation United States Vascular Endothelial Cell Viral Viral Load result Virus Replication Visual angiogenesis base conditional knockout corneal epithelium density experimental study immunopathology in vivo mouse model neovascularization neutrophil new therapeutic target novel therapeutic intervention pleiotropism response senescence

项目摘要

Herpes stromal keratitis (HSK) is a chronic inflammatory condition that develops in response to a recurrent corneal infection with herpes simplex virus-1 (HSV-1). HSK is the leading cause of infection-induced corneal blindness in the United States. Clinical manifestation of HSK involves the development of opacity and neovascularization into the avascular cornea. Newly formed leaky blood vessels in the corneal stroma obscure the visual axis, traffic the leukocytes (mostly neutrophils) into the inflamed cornea, and cause the corneal edema. The current mainstay of HSK treatment requires the long-term use of oral antiviral drugs and the topical application of steroids. The prolonged use of topical steroids causes a predisposition to herpetic reactivation, cataract development, and increased intraocular pressure (IOP), which may cause the development of glaucoma. A better understanding of cellular and molecular events involved in the pathogenesis of HSK could provide novel therapeutic targets to reduce the severity of HSK. The focus of this application is to understand the mechanisms by which Insulin-like growth factor binding protein-3 (IGFBP-3) regulates the pathogenesis of HSK. IGFBP-3 exerts its effect through insulin-like growth factor (IGF)-independent and-dependent mechanisms. In an IGF-independent manner, IGFBP-3 is known to induce cellular senescence. The cellular senescence is reported to inhibit viral replication. The IGF-dependent activity of IGFBP-3 involves sequestration of IGF-1 and IGF-2 molecules and limiting their bioavailability to IGF-1R, and thereby regulates IGF-1R signaling. Our preliminary results showed an elevated expression of IGFBP-3 in HSV-1 infected corneas of B6 mice, whereas a significantly reduced amount of IGFBP-3 protein was detected in the circulation of infected B6 mice when compared to uninfected B6 mice. The infected corneas of IGFBP-3 knockout (IGFBP-3 KO) mice showed an increased viral load. Besides, increased phosphorylation of IGF-1R, the first step in IGF-1R signaling, was determined in leukocytes infiltrating the HSK developing corneas of IGFBP-3 KO than B6 mice. A significant increase in hemangiogenesis and opacity was measured in infected corneas of IGFBP-3 KO than B6 mice. Together, these results led us to hypothesize that IGFBP-3 enhances viral clearance, reduces angiogenesis, and decreases the survival and effector function of myeloid cells in HSK developing corneas. Therefore, enhancing the IGFBP-3 protein level in HSV-1 infected cornea should alleviate the severity of HSK. Three aims are proposed to test our hypothesis. Aim I will test the hypothesis that hypoxia enhances IGFBP-3 expression in corneal epithelial cells, and an increased level of IGFBP-3 induces senescence in epithelial cells, and cellular senescence promotes HSV-1 clearance from the infected cornea. Aim II will test the hypothesis that IGF-1R signaling in myeloid and vascular endothelial cells control the severity of HSK. Aim III will test the hypothesis that increasing IGFBP-3 protein in HSV-1 infected cornea alleviates the severity of HSK.

疱疹性基质性角膜炎 (HSK) 是一种慢性炎症性疾病，是由于复发性角膜炎而发生的。单纯疱疹病毒 1 (HSV-1) 角膜感染是引起角膜感染的主要原因。在美国，HSK 的临床表现包括出现混浊和失明。角膜基质中新形成的渗漏血管变得模糊。视轴，将白细胞（主要是中性粒细胞）输送到发炎的角膜，并导致角膜水肿。目前HSK的治疗主要是长期口服抗病毒药物和外用药物。长期使用局部类固醇会导致疱疹复发，白内障的发生和眼内压（IOP）升高，这可能会导致白内障的发生更好地了解 HSK 发病机制中涉及的细胞和分子事件可以。提供新的治疗靶点来降低 HSK 的严重程度。该应用的重点是了解。胰岛素样生长因子结合蛋白 3 (IGFBP-3) 调节发病机制的机制 HSK。IGFBP-3 通过胰岛素样生长因子 (IGF) 独立和依赖机制发挥作用。已知 IGFBP-3 以不依赖于 IGF 的方式诱导细胞衰老。据报告可抑制病毒复制。IGFBP-3 的 IGF 依赖性活性涉及 IGF-1 和 IGF-1 的隔离。 IGF-2 分子并限制其对 IGF-1R 的生物利用度，从而调节 IGF-1R 信号传导。初步结果显示，HSV-1 感染的 B6 小鼠角膜中 IGFBP-3 的表达升高，而当受感染的 B6 小鼠的循环中检测到 IGFBP-3 蛋白的量显着减少时与未感染的 B6 小鼠相比，IGFBP-3 敲除 (IGFBP-3 KO) 小鼠的感染角膜表现出此外，IGF-1R 磷酸化的增加（IGF-1R 信号转导的第一步）是。在浸润HSK的白细胞中确定IGFBP-3 KO小鼠的角膜比B6小鼠显着。与 B6 小鼠相比，在 IGFBP-3 KO 的感染角膜中测量到血管生成和混浊度增加。总之，这些结果使我们得出结论，IGFBP-3 增强病毒清除，减少血管生成，并降低 HSK 发育角膜中骨髓细胞的存活和效应功能。提高 HSV-1 感染角膜中的 IGFBP-3 蛋白水平可减轻 HSK 的严重程度三个目标。目的是检验缺氧增强 IGFBP-3 表达的假设。角膜上皮细胞中 IGFBP-3 水平的增加会导致上皮细胞和细胞衰老衰老促进 HSV-1 从受感染的角膜中清除。 Aim II 将检验 IGF-1R 的假设。骨髓和血管内皮细胞中的信号传导控制 HSK 的严重程度，Aim III 将检验这一假设。增加 HSV-1 感染角膜中的 IGFBP-3 蛋白可减轻 HSK 的严重程度。