Comparative gynecology of Humans and Macaques

人类和猕猴的妇科比较

• 批准号: 7418079
• 负责人: Ronald S. Veazey
• 金额: $ 57.36万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-06 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7418079
• 关键词: Address; Affect; Agonist; Anatomy; Benchmarking; Biopsy; CCR5 gene; Cells; Cervical; Clinical; Clinical Trials; Collaborations; Comparative Study; Consensus; Data; Decision Making; Depth; Development; Diffuse; Disease; Dose; Experimental Models; Failure; Family suidae; Female; Future; Goals; Gynecology; HIV; HIV Infections; Human; Hyperplasia; Hysterectomy; Immune; Immune response; Immunologics; Immunology; Immunophenotyping; In Vitro; Infection; Inflammation; Label; Laboratories; Laboratory Animals; Lead; Liquid substance; Macaca; Macaca mulatta; Macaca nemestrina; Methodology; Methods; Microanatomy; Mitogens; Modeling; Mucosal Immune Responses; Mucous Membrane; Nonoxynol 9; Organ Culture Techniques; Penetration; Phase I Clinical Trials; Phenotype; Physiological; Physiology; Process; Production; RANTES; Rate; Reproductive Physiology; Research; Research Design; Research Project Grants; SIV; Safety; Screening procedure; Site; Staging; Standards of Weights and Measures; Sus scrofa; System; Tail; Testing; Time; Tissues; Translating; Ulcer; Vagina; Vaginal Douching; Viral; Virion; Woman; analog; cell type; cellulose sulfate; chemokine; clinically relevant; comparative; cytokine; human female; improved; in vivo; inhibitor/antagonist; microbicide; nonhuman primate; prevent; reproductive; research study; response; simian human immunodeficiency virus; tissue culture; tissue/cell culture; transmission process; vaginal transmission

Project 2 Worldwide, over 80% of HIV infections occur as a result of vaginal transmission. There is a desperate need for a safe and effective microbicide than can prevent the transmission of HIV to women. However, methods for screening potential microbicide candidates vary and include cell and tissue culture experiments to assess efficacy and nonhuman primate models for assessing efficacy and safety. However, methods vary between different laboratories regarding the types of cells and organ cultures used, various laboratories use different species of nonhuman primates. To date, no comparative studies have beejn. performed between/'normal''human, .female reproductive tissues and nonhuman primates, Thus,-it4s.not known-whether-microbicide studies-in nonhuman primates will be predictive of efficacy and safety in women. Furthermore, most vaginal explant studies of women used for assessing baseline levels of immune cells in the vagina, testing microbicide candidates, and studies of HIV transmission in vitro have invariably involved the use of tissues derived from hysterectomies, which are invariably diseased. Thus, inflammation, hyperplasia, ulcerations or other abnormalities may exist in such tissues that could affect the results of microbicide studies. The goal of Research Project 2 is to perform comparative studies of normal and hysterectomy-derived vaginal and cervical tissues of women to those of two species of macaques (rhesus and pigtails) to compare the anatomy and immunophenotype of immune cells and responses between female reproductive tissues of these species so that better informed decisions for microbicide testing can be made. We will also investigate the mechanisms of action of CCR5 inhibitors (RANTES analogs) in explant models using photoactivateable virions and labeled RANTES analogs to determine where blocking of these microbicide candidates takes place. The specific aims are to: Specific Aim 1: Compare the anatomy, immunology, and physiology of normal macaque and human female reproductive tissues using identical methodology; Specific Aim 2: Compare the immune responses of cervical explants of women, rhesus, and pig-tailed macaques to mitogens, potential microbicide candidates (RANTES analogs), and HIV/SIV using identical methodology, and; Specific Aim 3: Assess the depth of penetration and mechanisms of action of synthetic RANTES derivatives, and other CCR5 inhibitor microbicide candidates in human and macaque vaginal tissues.

项目 2 在世界范围内，超过 80% 的艾滋病毒感染是由阴道传播引起的。有一个 迫切需要一种安全有效的杀菌剂来防止艾滋病毒传播给妇女。 然而，筛选潜在杀菌剂候选物的方法各不相同，包括细胞和组织培养 评估功效的实验和评估功效和安全性的非人类灵长类动物模型。 然而，不同实验室对于细胞和器官培养类型的方法有所不同 不同的实验室使用不同种类的非人类灵长类动物。迄今为止，还没有比较研究 有蜜蜂。在/“正常”人类、雌性生殖组织和非人类灵长类动物之间进行， 因此，尚不清楚在非人类灵长类动物中进行的杀菌剂研究是否可以预测功效和 女性的安全。此外，大多数女性阴道外植体研究用于评估基线水平 阴道内免疫细胞的检测、候选杀菌剂测试以及艾滋病毒体外传播研究 总是涉及使用来自子宫切除术的组织，而这些组织总是患病的。 因此，这些组织中可能存在炎症、增生、溃疡或其他异常，从而可能导致 影响杀菌剂研究的结果。研究项目2的目标是进行比较研究 正常和子宫切除术衍生的女性阴道和宫颈组织与两种 猕猴（恒河猴和猪尾猴）比较免疫细胞的解剖结构和免疫表型 这些物种的雌性生殖组织之间的反应，以便做出更明智的决定 可以进行杀菌剂测试。我们还将研究CCR5抑制剂的作用机制 （RANTES 类似物）在外植体模型中使用光激活病毒颗粒和标记的 RANTES 类似物 确定这些候选杀菌剂的阻断发生的位置。具体目标是： 具体目标 1：比较正常猕猴和人类的解剖学、免疫学和生理学 使用相同方法的女性生殖组织； 具体目标 2：比较女性、恒河猴和猪尾巴的宫颈外植体的免疫反应 使用相同的方法对猕猴进行有丝分裂原、潜在的杀菌剂候选物（RANTES 类似物）和 HIV/SIV 的研究 方法论，以及； 具体目标 3：评估合成 RANTES 的渗透深度和作用机制 衍生物，以及人类和猕猴阴道组织中的其他 CCR5 抑制剂候选杀菌剂。