EXPERIMENTAL PATHOGENESIS & THERAPY OF OCULAR ADENOVIRUS

描述：(摘自申请者的摘要)腺病毒仍然是最 全球眼部外部感染的常见原因。快速传输速度 家庭、学校和工作导致显著的患者发病率和经济 损失。控制全球疫情和治疗患者的进展 随着我们兔子模型的发展而制作并成功 临床前研究测试一种有前景的新抗病毒药物，西多福韦。这个 具体目标是：1)确定其潜在的分子机制 腺病毒对抗病毒药物西多福韦的耐药性，并确定 这种耐药性对病毒致病的影响，2)确定 局部感染后腺病毒复制的解剖部位 兔眼。PI将决定逆行轴浆血流是否会 将腺病毒集中输送到同侧三叉神经节。如果 因此，它将为腺病毒在我们的模型中的使用奠定基础 用于基因治疗的神经基因递送载体。3)确定主机是否 细胞结合的特异性部分地解释了流行病学和 部分D组腺病毒亲眼性的实验差异 (Ad8、Ad19、Ad37)和呼吸衰退型C组腺病毒(Ad1、Ad2、Ad5、 Ad6)。这一目的将提供对腺病毒感染的更好的理解。 在细胞水平上具有潜在的新抗病毒应用 基于受体阻断和更好的宿主细胞基因靶向的治疗 治疗，以及4)评估是否有潜在的治疗作用 作为辅助物的局部抗炎和/或免疫调节剂 西多福韦抗病毒治疗对腺病毒眼病的优化治疗 使用兔子模型进行感染。总而言之，国际和平研究所提出了新的 应用细胞培养、角膜器官培养和动物的致病机制研究 模型以更好地了解眼部潜在的致病机制 疾病及其预防和治疗的方法。

DESCRIPTION: (from the applicant's abstract) Adenoviruses remain the most common cause of external eye infections worldwide. Rapid transmission at home, school, and at work lead to significant patient morbidity and economic losses. Progress toward controlling global epidemics and treating patients has been made with the development of our rabbit model and successful preclinical studies testing a promising new antiviral, cidofovir. The specific aims are: 1) To determine the underlying molecular mechanisms of adenovirus resistance to the antiviral, cidofovir, and to define the consequences of such resistance on viral pathogenesis, 2) To identify the anatomical sites of adenoviral replication following topical infection of the rabbit eye. The PI will determine if retrograde axoplasmic flow will transport adenovirus centrally to the ipsilateral trigeminal ganglion. If so, it will establish the use of adenovirus in our model as a possible neuronal gene delivery vector for gene therapy. 3) To determine if host cell binding specificity explains, in part, the epidemiological and experimental differences in oculotropism between select Group D adenoviruses (Ad8, Ad19, Ad37) and respiratropic Group C adenoviruses (Ad1, Ad2, Ad5, Ad6). This aim will provide a better understanding of adenovirus infection at the cellular level with potential applications for new antiviral therapies based on receptor blockade and better host cell targeting in gene therapy, and 4) To assess whether there is a potential therapeutic role for topical anti-inflammatory and/or immunomodulatory agents as adjuncts to cidofovir antiviral therapy in the optimal treatment of adenoviral ocular infections using the rabbit model. In summary, the PI proposes new pathogenesis studies using cell culture, corneal organ culture and an animal model to better understand the underlying pathogenic mechanisms of ocular disease and the means by which it may be prevented and treated.