Macaque studies

猕猴研究

• 批准号: 7134195
• 负责人: Ronald S. Veazey
• 金额: $ 54.68万
• 依托单位: IMMUNE DISEASE INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7134195
• 关键词: AIDS education /prevention; Macaca mulatta; RNA interference; antiAIDS agent; biological models; biopsy; biotechnology; cervix; chemokine receptor; communicable disease control; cooperative study; dosage; drug design /synthesis /production; drug screening /evaluation; endoscopy; female reproductive system disorder diagnosis; gene expression; human immunodeficiency virus; recombinant virus; sexually transmitted diseases; simian immunodeficiency virus; small interfering RNA; topical drug application

The goal of Research Project by Veazey (Nonhuman primate studies to develop an RNAi microbicide) is to evaluate the efficacy, safety, potency, and duration of effect of RNA interference (RNAi) technology in preventing vaginal transmission of HIV-1, using the simian/human immunodeficiency virus (SHIV) vaginal transmission model in rhesus macaques. The Leader will be Ronald Veazey, DVM, PhD, and the project will be located at the Tulane National Primate Research Center, Tulane, LA. For these studies, we will receive CCR5 specific RNAi from the Research Support Core which we will use in determining the depth or penetration, level of CCR5 downregulation, safety, and efficacy in preventing vaginal transmission of the CCR5 tropic SHIV162P3 virus to macaques when used as a microbicide. This project will coordinate closely with the leaders of the other research projects involved in testing these drugs in human explant and murine model systems (Research Projects by Lieberman and Palliser, and Research Support Cores). We will examine the safety and efficacy of the RNAi after topical application to the macaque vagina, by performing colposcopy and vaginal biopsy after vaginal administrations of the drugs to carefully rule out local inflammatory responses and to monitor levels of CCR5 expression in various tissues. CCR5 specific RNAi will also be assessed for its efficacy in downregulating CCR5 expression in vaginal and other tissues, as well as its efficacy and duration of effects in preventing vaginal SHIV transmission to macaques. The specific aims of research project by Veazey are to: Specific Aim 1. Determine whether siRNAs are efficiently taken up by vaginal and cervical tissues in the macaque and whether vaginal application of siRNAs silences macaque CCR5 expression in vivo; Specific Aim 2. Determine whether first generation, unmodified CCR5 siRNAs given before and after challenge with SHIV 162P3 protect against vaginal transmission; Specific Aim 3. Evaluate dose response to determine the amount of unmodified siRNA required to protect against challenge, and whether increasing amounts of siRNA cause vaginal irritation, inflammation, interferon induction or other unanticipated toxicity, and; Specific Aim 4. Determine whether optimized siRNAs against CCR5 and viral sequences alone and in combination provide superior protection than unmodified CCR5 siRNAs alone.

Veazey 研究项目（开发 RNAi 杀微生物剂的非人类灵长类动物研究）的目标是评估 RNA 干扰 (RNAi) 技术在预防疾病方面的功效、安全性、效力和持续时间 HIV-1 的阴道传播，利用猿/人类免疫缺陷病毒 (SHIV) 阴道传播 恒河猴模型。领导者将是 Ronald Veazey，DVM，博士，该项目将位于 杜兰国家灵长类动物研究中心，路易斯安那州杜兰。对于这些研究，我们将收到 CCR5 特定 来自研究支持核心的 RNAi，我们将使用它来确定深度或渗透、水平 CCR5 下调、预防 CCR5 热带阴道传播的安全性和有效性 用作杀菌剂时，SHIV162P3 病毒会感染猕猴。该项目将与 参与在人类外植体和小鼠模型中测试这些药物的其他研究项目的领导者 系统（Lieberman 和 Palliser 的研究项目以及研究支持核心）。我们将检查安全性和有效性 通过阴道镜检查和阴道活检，局部应用于猕猴阴道后进行 RNAi 阴道给药后仔细排除局部炎症反应并监测 不同组织中 CCR5 的表达水平。 CCR5 特异性 RNAi 的功效也将被评估 下调阴道和其他组织中 CCR5 的表达及其功效和持续时间 防止 SHIV 经阴道传播给猕猴。 Veazey 研究项目的具体目标是： 具体目标 1. 确定 siRNA 是否被阴道和宫颈组织有效吸收 猕猴以及阴道施用 siRNA 是否会沉默猕猴体内 CCR5 表达； 具体目标 2. 确定前后是否给予第一代、未修饰的 CCR5 siRNA SHIV 162P3 挑战可防止阴道传播； 具体目标 3. 评估剂量反应以确定保护所需的未修饰 siRNA 的量 对抗挑战，以及增加 siRNA 的量是否会导致阴道刺激、炎症、 干扰素诱导或其他意外毒性，以及； 具体目标 4. 确定针对 CCR5 和病毒序列的优化 siRNA 是否单独或在 组合提供比单独未修饰的 CCR5 siRNA 更好的保护。