STUDIES WITH ANIMAL MODELS OF SEXUALLY TRANSMITTED DISEASES

性传播疾病动物模型的研究

• 批准号: 6235333
• 负责人: Lawrence Raymond Stanberry
• 金额: $ 21.14万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-01 至 1998-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6235333
• 关键词: Cercopithecid herpesvirus 1; Chlamydiaceae; antibacterial agents; antiviral agents; capsaicin; chemoprevention; cholanate compound; disease /disorder model; disease /disorder prevention /control; guinea pigs; heparin; nonhuman therapy evaluation; northern blottings; polymerase chain reaction; pulmonary surfactants; quaternary ammonium compound; sexually transmitted diseases; surfactant

The chemoprophylaxis of sexually transmitted diseases (STD) is an attractive concept. Intravaginally administered drugs might prevent infection at the portal of entry by inactivating the organism; blocking attachment of penetration; or interfering with specialized functions essential in disease pathogenesis. To facilitate development of prophylactic strategies for controlling STD we will pursue three specific aims: First, polysulfated carbohydrates and surface-active shown in Projects 1 and 2 to have minimal cell toxicity but potent in vitro activity against HSV and/or chlamydia will be studied to determine if they can protect guinea pigs against experimental genital infection. Intravaginal inoculation of guinea pigs with HSV or chlamydia results in infection remarkably similar to that observed in humans. These models have been useful in exploring microbial pathogenesis and should predict the efficacy of topical microbicides in women. Second, we will use HSV mutants engineered in Project 1 to explore aspects of the pathogenesis of genital herpes potentially important in the development of topical microbicides. Using mutants deficient in glycoprotein C (gC), a component of the viral envelope important for virion attachment, we will determine whether gC is important in the pathogenesis of genital infection. This information will establish whether gC is a potential target for microbicidal action. If intravaginal microbicide are to be effective in preventing genital herpes, they must block entry of virus into sensory neurons. Since nothing is currently known regarding how virus enters sensory nerves we will use gB and gD deficient mutants to examine whether HSV directly binds and penetrates sensory nerve endings or gains access via cell-to- cell spread from epithelial cells. Third, we will investigate the mechanism by which prophylactic treatment with a synthetic isomer of capsaicin, civamide, protects animals against genital herpes. Intravaginal capsaicin does not block viral replication nor directly inactivate HSV but appears to alter pathogenesis by interfering with specialized virus-neuron interactions. Even brief treatment with capsaicin results in a prolonged effect on the pathogenesis of genital herpes. Information gained from these experiments may allow development of new topically active neuropharmacological agents that will be effective in preventing genital HSV infection. Thus, the goals of our studies are to develop topical microbicides that warrant further evaluation in clinical trials and to examine aspects of the pathogenesis of genital herpes that might facilitate the rational development of intravaginal chemoprophylactic agents designed to prevent genital HSV infection.

性传播疾病（STD）的化学预防是 有吸引力的概念。 阴道内给药药物可能会预防 通过灭活生物体在入境口发生感染；阻塞 渗透附着；或干扰专门功能 在疾病发病机制中至关重要。 为了促进发展 控制性传播疾病的预防策略，我们将采取三个具体措施 目标： 一、项目1所示的多硫酸化碳水化合物和表面活性剂 2 具有最小的细胞毒性，但具有有效的体外活性 将研究 HSV 和/或衣原体以确定它们是否可以保护 豚鼠抵抗实验性生殖器感染。 阴道内 豚鼠接种 HSV 或衣原体导致感染 与在人类中观察到的情况非常相似。 这些模型已 有助于探索微生物发病机制并可预测疗效 女性局部杀菌剂的研究。 其次，我们将使用项目1中设计的HSV突变体来探索以下方面 生殖器疱疹的发病机制可能具有重要意义 局部杀菌剂的开发。 使用缺乏的突变体 糖蛋白 C (gC)，病毒包膜的重要组成部分 病毒体附着，我们将确定 gC 在病毒颗粒附着中是否重要 生殖器感染的发病机制。 该信息将建立 gC是否是杀菌作用的潜在目标。 如果 阴道内使用杀微生物剂可有效预防生殖器感染 疱疹，它们必须阻止病毒进入感觉神经元。 自从 目前我们对病毒如何进入感觉神经一无所知 将使用gB和gD缺陷突变体来检查HSV是否直接 结合并穿透感觉神经末梢或通过细胞到- 细胞从上皮细胞扩散。 第三，我们将研究预防性治疗的机制。 含有辣椒素的合成异构体 civamide，可保护动物免受 生殖器疱疹。 阴道内辣椒素不会阻止病毒复制 也不直接灭活 HSV，但似乎通过以下方式改变发病机制 干扰专门的病毒-神经元相互作用。 甚至简短 辣椒素治疗会对发病机制产生长期影响 生殖器疱疹。 从这些实验中获得的信息可能允许 开发新的局部活性神经药理学药物， 能有效预防生殖器HSV感染。 因此，我们研究的目标是开发局部杀菌剂 需要在临床试验中进行进一步评估并检查以下方面 生殖器疱疹的发病机制可能有助于合理治疗 开发旨在预防的阴道内化学预防剂 生殖器HSV感染。