Experimental Pathogenesis & Therapy of Ocular Adenovirus

描述(申请人提供)：在21世纪，腺病毒(Ad)眼部感染仍然是一个严重的世界性问题，没有抗病毒治疗的选择。一个长期目标是开发一种有效的局部抗病毒药物来治疗腺病毒眼部感染。在这次竞争性的更新中，我们将在体外和我们的兔眼模型中评估几种有前景的抗病毒药物(ddC，NCT，CPE-C)，并确定临床开发的最佳候选药物。将解决对候选抗病毒药物出现耐药性的问题，并将在确定它们各自的抑制作用的分子机制后评估抗病毒药物之间临床上显著交叉耐药的可能性(S)。最后，我们将描述局部先天免疫最初保护眼睛免受腺病毒感染的作用。具体地说，我们将评估防御素类化合物的作用，包括α和β防御素，防御素样趋化因子(CXCL 10和CXCL 11)，以及中肠毒素。这些发病机制研究的结果将促进我们对腺病毒如何克服宿主防御成功建立眼部感染的了解。总而言之，有效的抗病毒治疗的发展应该会减轻患者的痛苦，限制流行病，并减少因旷工造成的经济、教育和其他社会损失。此外，更好地了解抗病毒耐药性和天然免疫宿主防御将使我们能够优化针对这种重要眼部病原体的治疗选择。

DESCRIPTION (provided by applicant): In the 21st century, adenovirus (Ad) ocular infections remain a significant worldwide problem for which there are no antiviral treatment options. One long term objective is to develop an effective topical antiviral to treat adenoviral ocular infections. In this competing renewal, we will evaluate several promising antivirals (ddC, NCT, CPE-C) in vitro and in our rabbit ocular model and determine the best candidate for clinical development. The issue of emerging resistance to candidate antivirals will be addressed and the possibility of clinically-significant cross resistance among antivirals will be assessed following the determination of their respective molecular mechanisn(s) of inhibitory action. Finally, we will characterize the role of local innate immunity that initially protects the eye from infection by adenovirus. Specifically, we will evaluate the role of defensin-like compounds including alpha and beta defensins, defensin-like chemokines (CXCL 10 and CXCL 11), and cathelicidins. The results of these pathogenesis studies will advance our knowledge of how adenovirus overcomes host defenses to successfully establish eye infections. In summary, the development of an effective antiviral treatment should lessen patient misery, limit epidemics, and reduce economic, educational and other societal losses from absenteeism. Furthermore, a better understanding of antiviral resistance and the innate immune host defenses will enable us to optimize our therapeutic options against this significant ocular pathogen.