STUDIES WITH ANIMAL MODELS OF SEXUALLY TRANSMITTED DISEASES

性传播疾病动物模型的研究

• 批准号: 6348899
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6348899
• 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.

局部杀菌剂的概念很有吸引力 - 一种安全有效的女性控制的产品，该产品旨在用于丢失的静脉内使用，并旨在保护妇女免于获得性传播疾病（STD）。 随着越来越多的化合物被确定为潜在的微生物，重要的是制定识别最有前途的候选者的策略。在项目1和2和核心B中进行的研究将鉴定具有针对重要的性病病原体和出色安全概况的出色体外抗菌活性的化合物。 在这个项目中，我们将使用生殖道感染的特征良好的动物模型研究选定的候选杀菌剂的功效和安全性。在特定的目标1中，我们将使用小鼠和豚鼠单纯疱疹病毒（HSV）和衣原体生殖道感染的模型来评估微生物限制颈椎阴道感染的能力，并且在生殖器疱疹模型的情况下，可以预防疾病。 使用这些模型，我们还将探索菌皮是否可以防止病原体扩散到重要的次要部位：对于HSV，到感觉神经节神经元；对于衣原体，到达上生殖器。 这些模型使我们探索了有前途的化合物在毛发前或后使用后的有效性。在特定的目标2中，我们将使用动物模型来检查微生物疗效如何受到体液的存在（例如血液或精液）的影响。 我们将通过确定微生物是否可以减少子宫颈阴道分泌物中存在的生物量以及通过开发和使用新的STD传播模型来减少菌心量来减少受感染妇女到易感男性伴侣的性病的传播。在特定目标3中，我们将探讨重要的安全问题，即微生物是否具有免疫毒性。 使用标准免疫学方法来评估生殖道免疫，我们将探索候选菌底剂影响先天免疫反应的潜力，这对于保护女性生殖道因性传播病原体的感染而言至关重要。这些研究将提供有关候选微​​生物在保护雌性动物免受两种重要性病病原体的体内有效性的重要信息。 这些实验还将探讨生体是否会影响雌性性病传播的问题，并研究微生物是否对女性生殖道免疫毒性的重要问题。 总的来说，这些研究将表征微生物的体内行为，并鉴定具有出色疗效和安全性概况的化合物。 总体而言，这项研究预计将产生信息，从而可以在临床试验中进行合理的生体优先级以进行进一步评估。