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.

从上一个R01资金期开始，我们产生了令人信服的新证据，即人类乙酰肝素酶-1 （HPSE）是一种硫酸乙酰肝素（HS）内吞酶酶，是负责触发血管生成的病毒因子 在单纯疱疹病毒类型1（HSV-1）感染期间，眼睛中的炎症。我们的体内研究表明 HPSE的存在可以显着增加眼科疾病的HSV-1复制和严重程度 预后。转录和蛋白质组学景观的研究显示了许多非酶作用 对于HSV-1感染期间的HPSE，并确定了可吸毒的新靶标。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限于促进病毒发病机理，而是在 蛋白激酶B（AKT）依赖性方式诱导炎症细胞死亡。使事情更加 有趣的，可能更重要的是，我们的新初步数据表明HPSE和AKT2同工型 在炎症细胞死亡和病毒产生中的缺乏症中，彼此的表观彼此相互彼此。因此，基于 我们对HPSE非酶角色和初步结果的发表观察结果，我们假设一个重要的， HSV-1介导的眼部注射，神经损伤， 以及由此产生的视力丧失。我们建议它们通过小分子抑制可以减少疾病 眼睛中的严重程度和病毒复制，并减少病毒脑炎的发病。该建议将集中 了解HPSE驱动的炎症细胞死亡机制和HSV-1期间AKT2的作用 角膜中的复制，传播和疾病病理。成功完成我们的研究将确定新的 以及更有效的HPSE和AKT2抑制剂，可减少炎症以及病毒负荷而不会引起病毒 任何不利影响。通过拟议的实验产生的结果将是广泛相关的，因为 HPSE活动已在各种眼科病理和其他神经退行性疾病中实施 以及多发性硬化症和阿尔茨海默氏病等疾病。