HPSE in Ocular Herpes Infection

HPSE 在眼部疱疹感染中的应用

• 批准号: 10753834
• 负责人: DEEPAK SHUKLA
• 金额: $ 42.28万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753834
• 关键词: Address; Adverse effects; Alzheimer' s Disease; Antiviral Agents; Binding; Biological Assay; Blindness; Cause of Death; Cell Death; Cells; Complex; Cornea; Corneal Diseases; Cyclic AMP-Dependent Protein Kinases; Cytoprotection; DNA Damage; DNA Repair; Data; Disease; Encephalitis; Environment; Epithelial Cells; Extracellular Matrix; Eye; Eye Infections; Eye diseases; Fatal Outcome; Funding; Genetic Transcription; Genotype; Growth Factor; Heparitin Sulfate; Herpesviridae Infections; Herpesvirus 1; Herpetic Keratitis; Human; Immunoprecipitation; Impairment; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Investigation; Knowledge; Mediating; Multiple Sclerosis; Mus; Nervous System; Neurodegenerative Disorders; Ocular Pathology; Pathology; Pathway interactions; Phenocopy; Phenotype; Phosphorylation; Phosphotransferases; Production; Prognosis; Protein Isoforms; Protein Kinase; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Publishing; Role; Severities; Severity of illness; Testing; Time; Tissues; Ulcer; Up-Regulation; Vascular Permeabilities; Viral; Viral Encephalitis; Viral Pathogenesis; Viral load measurement; Virulence Factors; Virus; Virus Replication; angiogenesis; corneal epithelium; cytokine; experimental study; heparanase; in vivo; inhibitor; knock-down; metabolomics; mimicry; mouse model; neovascularization; nerve damage; new therapeutic target; small molecule; transcriptomics

From the previous R01 funding period we have generated compelling new evidence that human Heparanase-1 (HPSE), a heparan sulfate (HS) endoglycosidase, is a virulence factor responsible for triggering angiogenesis and inflammation in the eye during herpes simplex virus type-1 (HSV-1) infection. Our in vivo studies have shown that HPSE presence can significantly increase HSV-1 replication and severity of ocular disease with poor prognosis. Investigation of transcriptional and proteomic landscapes revealed a multitude of non-enzymatic roles for HPSE during HSV-1 infection and identified new druggable targets. Upon further investigation, we found that the significance of HPSE in corneal infection may not be limited to promoting viral pathogenesis only, but also in the induction of inflammatory cell death in a protein kinase B (Akt) dependent manner. Making things even more interesting and potentially more significant, our new preliminary data suggests that HPSE and Akt2 isoform phenocopy each other both in inflammatory cell death and deficiency in virus production. Therefore, based on our published observations of HPSE’s non-enzymatic roles and preliminary results, we hypothesize an important, yet interconnected regulatory role for HPSE and Akt2 in HSV-1 mediated ocular inflammation, nerve damage, and the resultant vision loss. We propose that their inhibition through small molecules can reduce disease severity and viral replication in the eye and reduce the incidences of viral encephalitis. This proposal will focus on understanding HPSE driven inflammatory cell death mechanisms and the role for Akt2 during HSV-1 replication, spread and disease pathology in the cornea. Successful completion of our studies will identify new and more effective HPSE and Akt2 inhibitors that can reduce inflammation as well as virus load without causing any adverse effects. Results generated through the proposed experiments will be broadly relevant, as aberrant HPSE activity has been implicated in a wide array of ocular pathologies and other neurodegenerative diseases and disorders such as multiple sclerosis and Alzheimer’s Disease.

从之前的 R01 资助期中，我们获得了令人信服的新证据，表明人类 Heparanase-1 (HPSE) 是一种硫酸乙酰肝素 (HS) 糖苷内切酶，是负责触发血管生成的毒力因子 以及 1 型单纯疱疹病毒 (HSV-1) 感染期间眼部炎症。我们的体内研究表明 HPSE 的存在可以显着增加 HSV-1 的复制和眼部疾病的严重程度 预后。对转录和蛋白质组景观的研究揭示了多种非酶作用 HSV-1 感染期间的 HPSE 并确定了新的药物靶点。经过进一步调查，我们发现 HPSE 在角膜感染中的重要性可能不仅限于促进病毒发病机制，还包括 以蛋白激酶 B (Akt) 依赖性方式诱导炎症细胞死亡。让事情变得更加美好 有趣且可能更重要的是，我们的新初步数据表明 HPSE 和 Akt2 亚型 在炎症细胞死亡和病毒产生缺陷方面彼此表现型相似。因此，基于 根据我们发表的对 HPSE 非酶作用的观察结果和初步结果，我们假设一个重要的， HPSE 和 Akt2 在 HSV-1 介导的眼部炎症、神经损伤、 以及由此导致的视力丧失。我们认为通过小分子抑制它们可以减少疾病 严重程度和病毒在眼睛中的复制，并减少病毒性脑炎的发病率。该提案将重点 了解 HPSE 驱动的炎症细胞死亡机制以及 Akt2 在 HSV-1 期间的作用 角膜中的复制、传播和疾病病理学。成功完成我们的研究将发现新的 以及更有效的 HPSE 和 Akt2 抑制剂，可以减少炎症和病毒载量，而不会引起 任何不良影响。通过所提出的实验产生的结果将具有广泛的相关性，因为异常 HPSE 活性与多种眼部病变和其他神经退行性疾病有关 以及多发性硬化症和阿尔茨海默病等疾病。