STUDIES WITH ANIMAL MODELS OF SEXUALLY TRANSMITTED DISEASES

性传播疾病动物模型的研究

• 批准号: 6201242
• 负责人: Lawrence Raymond Stanberry
• 金额: $ 19.95万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6201242
• 关键词: Herpes simplex disease; antibacterial agents; antiviral agents; chemoprevention; chlamydial disease; communicable disease transmission; disease /disorder model; drug screening /evaluation; female; genital secretion; guinea pigs; immunotoxicity; laboratory mouse; nonhuman therapy evaluation; sexually transmitted diseases; vagina

The concept of the topical microbicide is attractive - a safe and effective, female-controlled product destined for intravaginal use and intended to protect women from acquiring sexually transmitted diseases (STDs). With an increasing number of compounds identified as potential microbicides it is important to develop strategies for identifying the most promising candidates. Studies in Projects 1 and 2 and Core B will identify compounds with excellent in vitro antimicrobial activity against important STD pathogens and outstanding safety profiles. In this project we will investigate the efficacy and safety of selected candidate microbicides using well-characterized animal model of genital tract infection. In specific aim 1 we will use mouse and guinea pig models of herpes simplex virus (HSV) and chlamydial genital tract infection to assess the ability of microbicides to limit cervico-vaginal infection and, in the case of the genital herpes models, prevent disease. Using these models we will also explore whether microbicides can prevent spread of the pathogen to important secondary sites: for HSV, to sensory ganglion neurons; and for chlamydia, to the upper genital tract. These models allow us explore the effectiveness of promising compounds for either pre- or post-coital use. In specific aim 2 we will use animal models to examine how microbicides efficacy can be affected by the presence of body fluids (e.g. blood or semen). We will explore whether microbicides might reduce STD transmission from infected women to susceptible male partners by determining whether microbicides can reduce the amount of organism present in cervico-vaginal secretions and by developing and using new murine models of STD transmission. In specific aim 3 we will explore the important safety issue of whether microbicides are immunotoxic. Using standard immunological methods to assess genital tract immunity, we will explore the potential of candidate microbicides to impact innate immune responses known to be important in protecting the female genital tract against infection by sexually transmitted pathogens. These studies will provide important information regarding the in vivo effectiveness of candidate microbicides in protecting female animals against two important STD pathogens. These experiments will also explore the issue of whether microbicides can impact female to male STD transmission and investigate the important question of whether microbicides are immunotoxic to the female genital tract. Collectively, theses studies will characterize the in vivo behavior of microbicides and identify compounds with outstanding efficacy and safety profiles. Overall, this research is expected to yield information that will allow for the rational prioritization of microbicides for further evaluation in clinical trials.

外用杀菌剂的概念很有吸引力——一种安全有效、女性控制的产品，用于阴道内使用，旨在保护女性免受性传播疾病（STD）的侵害。 随着越来越多的化合物被确定为潜在的杀菌剂，制定策略来识别最有希望的候选化合物非常重要。项目 1 和 2 以及核心 B 的研究将确定对重要 STD 病原体具有优异体外抗菌活性和出色安全性的化合物。 在该项目中，我们将使用充分表征的生殖道感染动物模型来研究所选候选杀菌剂的功效和安全性。在具体目标 1 中，我们将使用单纯疱疹病毒 (HSV) 和衣原体生殖道感染的小鼠和豚鼠模型来评估杀菌剂限制宫颈阴道感染的能力，以及在生殖器疱疹模型的情况下预防疾病的能力。 使用这些模型，我们还将探索杀菌剂是否可以阻止病原体传播到重要的二级部位：对于HSV，传播到感觉神经节神经元；对于HSV，传播到感觉神经节神经元；对于HSV，传播到感觉神经节神经元；对于衣原体，则感染上生殖道。 这些模型使我们能够探索有前景的化合物在性交前或性交后使用的有效性。在具体目标 2 中，我们将使用动物模型来研究体液（例如血液或精液）的存在如何影响杀菌剂的功效。 我们将通过确定杀菌剂是否可以减少宫颈阴道分泌物中存在的微生物数量以及开发和使用新的 STD 传播小鼠模型来探索杀菌剂是否可以减少从受感染女性到易感男性伴侣的 STD 传播。在具体目标 3 中，我们将探讨杀菌剂是否具有免疫毒性这一重要的安全问题。 使用标准免疫学方法来评估生殖道免疫力，我们将探索候选杀菌剂影响先天免疫反应的潜力，该先天免疫反应对于保护女性生殖道免受性传播病原体感染非常重要。这些研究将提供有关候选杀菌剂在保护雌性动物免受两种重要性病病原体侵害方面的体内有效性的重要信息。 这些实验还将探讨杀菌剂是否会影响女性向男性性病传播的问题，并研究杀菌剂是否对女性生殖道具有免疫毒性的重要问题。 总的来说，这些研究将表征杀菌剂的体内行为，并确定具有出色功效和安全性的化合物。 总体而言，这项研究预计将产生信息，以便合理确定杀菌剂的优先顺序，以便在临床试验中进行进一步评估。