HPSE in Ocular Herpes Infection

从之前的R 01资助期，我们已经产生了令人信服的新证据，表明人类乙酰肝素酶-1 （HPSE），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 以及在1型单纯疱疹病毒（HSV-1）感染期间眼睛中的炎症。我们的体内研究表明 HPSE存在可显著增加HSV-1复制和眼部疾病的严重性， 预后转录和蛋白质组学的研究揭示了许多非酶的作用 用于HSV-1感染期间的HPSE，并确定了新的可药用靶点。经过进一步调查，我们发现， HPSE在角膜感染中的意义可能不仅限于促进病毒致病， 以蛋白激酶B（Akt）依赖性方式诱导炎性细胞死亡。使事情变得更加 有趣的和潜在的更重要的是，我们的新的初步数据表明，HPSE和Akt 2亚型， 在炎性细胞死亡和病毒产生缺陷方面彼此表型相似。所以基于 我们发表的HPSE的非酶作用的观察和初步结果，我们假设一个重要的， HPSE和Akt 2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。我们提出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驱动的炎性细胞死亡机制和Akt 2在HSV-1过程中的作用 角膜中的复制、传播和疾病病理学。成功完成我们的研究将确定新的 和更有效的HPSE和Akt 2抑制剂，可以减少炎症以及病毒载量，而不会引起 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，作为异常的 HPSE活性与多种眼部病理和其他神经退行性疾病有关 以及诸如多发性硬化症和阿尔茨海默氏病之类的疾病。

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.