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）的化学预防是一种 有吸引力的概念。 阴道内给药可能会阻止 通过使有机体失活而在入口处感染;阻塞 插入附件;或干扰专门功能 在疾病发病机制中至关重要。 为促进 为控制性病，我们将采取三个具体的预防策略， 目的： 首先，多硫酸化碳水化合物和表面活性剂如项目1所示 和2具有最小的细胞毒性，但在体外具有有效的抗 将研究HSV和/或衣原体，以确定它们是否能保护 豚鼠对实验性生殖器感染。 阴道内 用HSV或衣原体接种豚鼠会导致感染 与在人类中观察到的非常相似。 这些模型已经 有助于探索微生物的发病机制，并应预测疗效 女性外用杀菌剂。 其次，我们将使用项目1中工程化的HSV突变体来探索 生殖器疱疹的发病机制可能在 局部杀微生物剂的发展。 使用缺乏 糖蛋白C（gC），病毒包膜的一种成分，对 病毒体附着，我们将确定gC是否在 生殖器感染的发病机制。 这些信息将建立 gC是否是杀微生物作用的潜在靶标。 如果 阴道内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。 以来 目前还不知道病毒是如何进入感觉神经的， 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- 细胞从上皮细胞扩散。 第三，我们将研究预防性治疗的机制， 与辣椒素的合成异构体，civamide，保护动物， 生殖器疱疹 阴道内辣椒素不能阻断病毒复制 也不直接抑制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。 即使是短暂 用辣椒素治疗导致对发病机制的长期影响 生殖器疱疹的 从这些实验中获得的信息可以让 开发新的局部活性神经药理学药物， 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微生物剂， 需要在临床试验中进一步评估，并检查 生殖器疱疹的发病机制，可能有助于合理的 设计用于预防的阴道内化学预防剂的开发 生殖器HSV感染