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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：
10468069
负责人：
Susmit Suvas
金额：
$ 36.34万
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/10468069
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.

疱疹性角膜基质炎（HSK）是一种慢性炎症性疾病，单纯疱疹病毒（HSV-HSV-1）是引起角膜感染的主要原因 HSK的临床表现包括混浊的发展，新生血管进入无血管的角膜。角膜基质中新形成的渗漏血管不明显视轴，运输白细胞（主要是中性粒细胞）进入发炎的角膜，并导致角膜水肿。目前HSK治疗的主要方法是长期口服抗病毒药物和局部外用抗病毒药物。类固醇的应用。长期使用局部类固醇会导致疱疹复发的倾向，白内障的发展，以及眼内压（IOP）升高，这可能导致更好地理解HSK发病机制中涉及的细胞和分子事件，提供新的治疗靶点，以降低HSK的严重程度。本申请的重点是了解胰岛素样生长因子结合蛋白-β 3（IGFBP-BP 3）调节糖尿病发病机制的研究进展 IGFBP-β 3通过胰岛素样生长因子（IGF-β）-β非依赖性和-β依赖性机制发挥其作用. 已知IGFBP-BP 3以不依赖于IGF-1的方式诱导细胞衰老。 IGFBP-CRP 3的IGF-CRP依赖性活性涉及IGF-CRP 1和IGF-CRP 2的螯合， IGF-12分子并将其生物利用度限制为IGF-1 R，从而调节IGF-1 R信号传导。我们的初步结果显示，IGFBP-B13在B6小鼠HSV-B11感染的角膜中表达升高，而在感染的B6小鼠的循环中检测到IGFBP-B13蛋白的量显著减少，与未感染的B6小鼠相比，IGFBP-B13基因敲除小鼠感染的角膜显示出明显的免疫抑制作用。此外，IGF-1 R信号转导的第一步，IGF-1 R磷酸化的增加，在浸润IGFBP-B13 KO小鼠HSK发育角膜的白细胞中，与B6小鼠相比，在IGFBP-B13 KO小鼠感染的角膜中测量到血管生成和混浊的增加。总之，这些结果使我们假设IGFBP-BMP 3增强病毒清除，减少血管生成，并降低HSK发育角膜中髓样细胞的存活和效应功能。因此，提高HSV-E11感染角膜中IGFBP-E13蛋白水平可减轻HSK的严重程度。目的验证缺氧促进IGFBP-G3表达的假说在角膜上皮细胞中，IGFBP-BMP 3水平的增加诱导上皮细胞衰老，衰老促进HSV-1 R从感染的角膜中清除。目的II将检验IGF-1 R 髓系细胞和血管内皮细胞的信号传导控制HSK的严重程度。目的III将验证这一假设 HSV-11感染角膜中IGFBP-13蛋白的升高可加重HSK的严重程度。