ROLE OF CELL INTEGRINS IN ADENOVIRAL CONJUNCTIVITIS

项目总结/摘要 人腺病毒是呼吸道、胃肠道 还有眼睛在严重的眼部感染病例中，如流行性感冒中发生的病例， 在角膜结膜炎中，腺病毒可引起显著的发病率和视力丧失。在 目前，即使有有效的抗病毒药物也很少被批准用于治疗 腺病毒眼部感染本文提出的研究试图通过资本化来纠正这种情况。 上一个资助期取得的重大进展，以及我们新的初步 问题研究具体而言，我们建议对这些问题进行系统和多学科的调查。 天然存在的抗微生物肽（AMP）和新的合成小分子的抗病毒活性 分子。所提出的研究的主要目标是精确地确定AMP和合成的AMP是如何在细胞中表达的。 小分子干预腺病毒细胞进入途径。这一目标将通过以下方式实现： 1)鉴定被AMP和合成分子识别的腺病毒外壳蛋白; 2)分析AMP与腺病毒的精确结合特性; 3）求解AMP与腺病毒的三维结合特性， 通过X射线衍射和冷冻电子显微镜观察腺病毒-AMP复合物的结构;以及 4)采用组合文库的高通量筛选来发现新的合成小分子， 限制腺病毒感染的分子。这些调查不仅应该改善我们的 了解腺病毒结构和参与宿主细胞进入的机制，但也可能导致 涉及腺病毒诱导的眼部疾病的新治疗方法的开发。

Project Summary/Abstract Human adenoviruses are major causes of acute infections of the respiratory, gastrointestinal tract, and the eye. In severe cases of ocular infections, such as those occurring in epidemic keratoconjunctivitis, adenovirus can cause significant morbidity and loss of visual acuity. At the present time, there are few if any effective antiviral agents that have been approved for the treatment of adenovirus eye infections. The studies proposed here seek to remedy this situation by capitalizing on the significant progress made during the previous funding period as well as our new preliminary studies. Specifically, we propose to undertake a systematic and multidisciplinary investigation of the antiviral activities of naturally occurring antimicrobial peptides (AMPs) and novel synthetic small molecules. The major goal of the proposed studies is to determine precisely how AMPs and synthetic small molecules intervene in the adenovirus cell entry pathway. This goal will be achieved by: 1) identifying the adenoviral coat proteins that are recognized by AMPs and synthetic molecules; 2) analyzing the precise adenovirus binding properties of AMPs; 3) solving the three-dimensional structure of adenovirus-AMP complexes by X-ray diffraction and cryoelectron microscopy; and 4) employing high-throughput screens of combinatorial libraries to discover novel synthetic small molecules that restrict adenovirus infection. These investigations should not only improve our knowledge of adenovirus structure and the mechanisms involved in host cell entry but could also lead to the development of new treatments for adenovirus-induced ocular diseases.