EXPERIMENTAL PATHOGENESIS & THERAPY OF OCULAR ADENOVIRUS

描述：（来自申请人的摘要）腺病毒仍然是最常见的 全球常见的外眼感染原因。 快速传输. 家庭、学校和工作场所导致显著的患者发病率和经济损失， 损失 在控制全球流行病和治疗患者方面取得的进展 已经取得了与我们的兔子模型的发展和成功 临床前研究测试一种有前途的新的抗病毒药物西多福韦。 的 具体目标是：1）确定潜在的分子机制， 腺病毒对抗病毒药物西多福韦的耐药性，并确定 这种耐药性对病毒发病机制的影响，2）为了确定 局部感染后腺病毒复制的解剖部位 兔子的眼睛 PI将确定逆行轴浆流是否 将腺病毒集中运输到同侧三叉神经节。 如果 因此，它将在我们的模型中建立腺病毒的使用作为一种可能， 用于基因治疗的神经元基因递送载体。 3)要确定主机是否 细胞结合特异性部分解释了流行病学和 选定D组腺病毒之间向眼性的实验差异 (Ad8，Ad 19，Ad 37）和嗜热性C组腺病毒（Ad 1，Ad 2，Ad 5， Ad6）。 这一目标将提供更好的了解腺病毒感染 在细胞水平上， 基于受体阻断和更好的宿主细胞靶向基因治疗 治疗，以及4）评估是否有潜在的治疗作用， 局部抗炎剂和/或免疫调节剂， 西多福韦抗病毒治疗的最佳治疗腺病毒眼 使用兔子模型的感染。 总之，PI提出了新的 使用细胞培养物、角膜器官培养物和动物的发病机理研究 模型，以更好地了解潜在的致病机制， 疾病及其预防和治疗方法。

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.