Comparative gynecology of Humans and Macaques

人类和猕猴的妇科比较

• 批准号: 8066954
• 负责人: Ronald S. Veazey
• 金额: $ 58.44万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8066954
• 关键词: Address; Affect; Agonist; Anatomy; Benchmarking; Biopsy; CCR5 gene; Cells; Cervical; Clinical; Clinical Trials; Collaborations; Comparative Study; Consensus; Data; Decision Making; 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; Reproductive Physiology; Research; Research Design; Research Project Grants; SIV; Safety; Screening procedure; Site; Staging; 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.

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