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：
10673185
负责人：
Susmit Suvas
金额：
$ 37.46万
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/10673185
关键词：
Ablation Adrenal Cortex Hormones Antiviral Agents Biological Assay Biological Availability Blindness Blocking Antibodies Blood Vessels Cataract Cell Aging Cell surface Cells Chronic Circulation Clinical Confocal Microscopy Cornea Corneal Stroma Corneal edema Development Disease Enzyme-Linked Immunosorbent Assay Epithelial Cells Event Eye Infections Glaucoma Goals Herpes stromal keratitis Herpesvirus 1 Human Hypoxia 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 Knock-out Knockout Mice Knowledge Lesion Leucocytic infiltrate 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 Transfection Tyrosine Kinase Inhibitor Tyrosine Phosphorylation United States Vascular Endothelial Cell Viral Viral Load result Virus Replication Visual angiogenesis conditional knockout corneal epithelium density experimental study immune modulating agents 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.

疱疹基质角膜炎（HSK）是一种慢性炎症疾病，响应于复发性的发展用单纯疱疹病毒1（HSV-1）感染角膜感染。 HSK是感染引起的角膜的主要原因美国的失明。 HSK的临床表现涉及不透明度的发展和新生血管形成血管角膜。角膜基质中新形成的漏水血管晦涩视觉轴，白细胞（主要是中性粒细胞）流入发炎的角膜，并引起角膜水肿。 HSK治疗的当前主要需要长期使用口服抗病毒药物和局部使用类固醇的应用。长时间使用局部类固醇会导致疱疹复活的易感性，白内障发育和增加的眼内压（IOP），这可能导致青光眼。更好地了解涉及HSK发病机理的细胞和分子事件可以提供新颖的治疗靶标，以降低HSK的严重性。该应用的重点是了解胰岛素样生长因子结合蛋白-3（IGFBP-3）的机制调节了 HSK。 IGFBP-3通过胰岛素样生长因子（IGF）独立和依赖性机制发挥其作用。已知IGFBP-3以IGF非依赖性方式诱导细胞感应。细胞感应是报告抑制病毒复制。 IGFBP-3的IGF依赖性活性涉及IGF-1和 IGF-2分子并将其生物利用度限制为IGF-1R，从而调节IGF-1R信号传导。我们的初步结果表明，在HSV-1感染B6小鼠的角膜中IGFBP-3的表达升高，而在感染的B6小鼠的循环中检测到IGFBP-3蛋白的量显着降低。与未感染的B6小鼠相比。 IGFBP-3敲除（IGFBP-3 KO）的感染角膜显示病毒负荷增加。此外，IGF-1R的磷酸化增加，IGF-1R信号的第一步是在白细胞中确定的，渗入与B6小鼠相比，发育于IGFBP-3 KO的HSK。重要的与B6小鼠相比，在感染的IGFBP-3 KO角膜中测量了血管生成和不透明度的增加。总之，这些结果使我们假设IGFBP-3增强了病毒清除率，减少了血管生成，并降低hsk发育角膜的髓样细胞的存活和效应子功能。所以，增强HSV-1感染角膜中IGFBP-3蛋白水平应减轻HSK的严重程度。三个目标提议检验我们的假设。目的我将测试缺氧增强IGFBP-3表达的假设在角膜上皮细胞中，IGFBP-3的水平升高会诱导上皮细胞和细胞的感应传感可促进受感染角膜的HSV-1清除。 AIM II将检验IGF-1R的假设髓样和血管内皮细胞中的信号传导控制HSK的严重程度。 AIM III将检验假设在HSV-1感染的角膜中增加IGFBP-3蛋白可以减轻HSK的严重程度。