Animal Models

动物模型

• 批准号: 8993314
• 负责人: HOWARD S FOX
• 金额: $ 28.6万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8993314
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Adherence; Anatomy; Animal Experimentation; Animal Experiments; Animal Model; Animals; Anti-Retroviral Agents; Atazanavir; Back; Biochemical; Biodistribution; Biological Markers; Biopsy; Blood; Brain; Cells; Clinical; Collaborations; Combined Modality Therapy; Development; Disease; Dissection; Dose; Drug Formulations; Drug Kinetics; Drug or chemical Tissue Distribution; Excipients; Failure; Genome; Goals; Grant; HIV; HIV-1; Homeostasis; Human; Immune; Infection; Injection of therapeutic agent; Integrase; Integrase Inhibitors; Lamivudine; Ligands; Link; Macaca; Macaca mulatta; Measures; Medicine; Metabolic; Molecular; Monkeys; Mus; Organ; Pathogenesis; Pharmaceutical Preparations; Pharmacodynamics; Physiology; Polymers; Process; Prodrugs; Property; Prophylactic treatment; Protein Binding; Rectum; Research Personnel; Residual state; Rest; Ritonavir; Rodent; Rodent Model; Safety; Scheme; Shapes; Site; Testing; Therapeutic; Tissues; Toxicology; Translations; Tryptophan 2,3 Dioxygenase; Validation; Viral; Virus; Virus Diseases; Work; abacavir; abstracting; antiretroviral therapy; base; bench to bedside; bioimaging; efficacy evaluation; efficacy testing; improved; inhibitor/antagonist; lymph nodes; magnetite ferrosoferric oxide; metabolomics; molecular imaging; nanoformulation; nanoparticle; nonhuman primate; novel; programs; rectal; research study; safety testing; success; tissue processing

Core C Abstract: Long-acting nanoformulated antiretroviral therapy (nanoART) is poised for bench to bedside clinical translation. However, hurdles remain to see nanoART as a significant part of the therapeutic armamentarium. This includes, but is not limited to, evidence for improved dosing, tissue biodistribution and pharmacodynamics (PD). All require support from readily available and affordable rodent models of human immunodeficiency virus (HIV)-infection for PD and pharmacokinetic (PK) and antiretroviral efficacy tests as performed on non- human primates. To these ends, the Core C animal model core will provide humanized mice for efficacy evaluation and rhesus macaques for PK and tissue distribution testing and pilot efficacy studies. The purpose is to assist researchers with animal experiments (Projects 2 and 3 and Core B). These will include assessments of viral and immune parameters, tissue dissections and when relevant, biopsies of lymph nodes and rectal tissues. All will be processed, in collaborative experiments, for molecular, virologic and biochemical studies. The goal of the humanized mice component is to assess direct antiretroviral efficacy and HIV eradication experiments of selected and drug formulation combinations. Based on the program needs specific formulations will contain GSK744 and GSK8232, an integrase and maturation inhibitor, respectively, or mixtures of both. Alternatively, prodrugs of 3TC, abacavir, maraviroc, and ritonavir-boosted atazanavir will be used, in part, as combination therapy. These nanoformulations or their combinations will be tested for their abilities to reduce residual virus or eradicate HIV when administered with indoleamine 2, 3-dioxygenase inhibitors in platform development. Humanized mice will be employed for metabolomics and molecular imaging studies in order to provide rapid assessments of drug success or failures as they can assess tissue homeostasis and predict end organ disease. Non-human primates will be made available, specifically for drug PK, tissue distribution and toxicological studies. Tissue distribution will be assessed in bioimaging experiments (Project 3) by ligand-targeted magnetite nanoformulations and linked back to PK and PD tests as contained in Projects 1, 2 and Core B.

核心C摘要： 长效纳米成型抗逆转录病毒疗法（NANOART）有望进行长凳上的床边临床翻译。 但是，仍然将障碍视为治疗武器群的重要组成部分。这 包括但不限于改善剂量，组织生物分布和药效学的证据 （PD）。所有这些都需要从人类免疫缺陷的随时可用和负担得起的啮齿动物模型的支持 PD和药代动力学（PK）和抗逆转录病毒疗效测试的病毒（HIV）感染。 人类灵长类动物。到这些目的，核心C动物模型核心将提供人源化的小鼠功效 用于PK和组织分布测试和初步疗效研究的评估和恒河猕猴。目的 是为了帮助研究人员进行动物实验（项目2和3和核心B）。这些将包括 评估病毒和免疫参数，组织解剖以及相关时，淋巴结活检 和直肠组织。在协作实验中，所有这些都将用于分子，病毒和生化 研究。人性化小鼠成分的目的是评估直接抗逆转录病毒功效和HIV 根除选定和药物配方组合的实验。基于程序需要特定的 配方将包含GSK744和GSK8232，分别是整合酶和成熟抑制剂，或 两者的混合物。或者，3TC，Abacavir，Maraviroc和Ritonavir促进的Atazanavir的前药将是 部分用作联合疗法。这些纳米制剂或其组合将被测试 用吲哚胺2、3-二氧酶施用时，能够减少残留病毒或根除HIV的能力 平台开发中的抑制剂。人源化小鼠将用于代谢组学和分子成像 研究以提供对药物成功或失败的快速评估，因为它们可以评估组织 稳态并预测最终器官疾病。非人类灵长类动物将被提供，专门用于药物 PK，组织分布和毒理学研究。组织分布将在生物成像实验中评估 （项目3）由靶向配体的磁铁矿纳米制剂，并链接回PK和PD测试 项目1、2和核心B。