Macaque studies

猕猴研究

• 批准号: 7928124
• 负责人: Ronald S. Veazey
• 金额: $ 72.16万
• 依托单位: IMMUNE DISEASE INSTITUTE, INC.
• 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/7928124
• 关键词: Adoptive Transfer; Affect; Animal Model; Animals; Area; Autopsy; Biological Models; Biopsy; CCR5 gene; Cells; Cervical; Colposcopy; Confocal Microscopy; Dendritic Cells; Doctor of Philosophy; Dose; Down-Regulation; Epidemic; Epithelium; Flow Cytometry; Generations; Goals; HIV; HIV Infections; HIV-1; Human; Immunohistochemistry; In Vitro; Infection; Inflammation; Inflammatory Response; Interferons; Label; Long-Term Effects; Lymphocyte; Macaca; Macaca mulatta; Modeling; Monitor; Mononuclear; Mucous Membrane; Mus; Penetration; Peripheral Blood Lymphocyte; Phenotype; Plasma; Prevent viral transmission; Primates; Progesterone; RNA; RNA Interference; Recruitment Activity; Research; Research Project Grants; Research Support; Safety; Sampling; Small Interfering RNA; Structure; Surface; T-Lymphocyte; Technology; Testing; Tissues; Topical application; Toxic effect; Vagina; Vaginal Drug Administration; Viral; Viral Load result; Virus; Woman; base; chemokine receptor; design; drug testing; efficacy testing; in vivo; irritation; macrophage; microbicide; nonhuman primate; prevent; prophylactic; receptor expression; research study; response; simian human immunodeficiency virus; systems research; transmission process; vaginal transmission

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的研究项目（非人类灵长类动物研究以开发RNAi菌心）是为了评估 RNA干扰（RNAi）技术的疗效，安全性，效力和持续时间在防止 使用Simian/人类免疫缺陷病毒（SHIV）阴道传播的HIV-1阴道传播 猕猴中的模型。领导者将是Ronald Veazey，DVM，PhD，该项目将位于 图拉恩国家灵长类动物研究中心，路易斯安那州杜兰市。对于这些研究，我们将获得CCR5特定的 RNAi来自研究支持核心，我们将用于确定深度或渗透率，水平 CCR5下调，安全性和防止CCR5热带阴道传播的功效 SHIV162P3病毒用作猕猴。该项目将与 其他研究项目的领导者在人类外观和鼠模型中测试这些药物 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功效 局部应用到猕猴阴道后的RNAi，通过进行阴道镜检查和阴道活检 在阴道施用药物后，仔细排除当地炎症反应并监测 各种组织中CCR5表达的水平。 CCR5特异性RNAi也将评估其在 下调阴道和其他组织中的CCR5表达及其功效和效果持续时间 防止阴道湿腹猕猴传播。 Veazey研究项目的具体目的是： 具体目的1。确定siRNA是否被阴道和宫颈组织有效地吸收 猕猴以及阴道siRNAS在体内是否在体内表达猕猴CCR5表达； 特定目标2。确定第一代未修饰的CCR5 siRNA是否在之前和之后给出 SHIV 1623的挑战防止阴道传播； 特定目标3。评估剂量反应以确定保护所需的未修饰siRNA量 反对挑战，以及增加的siRNA是否引起阴道刺激，炎症， 干扰素诱导或其他意外毒性，以及； 特定目标4。确定是否仅针对CCR5和病毒序列进行优化的siRNA 组合比单独的CCR5 siRNA提供了优越的保护。