Characterization of a humanized mouse model to study HIV and ARV effects on bone

研究 HIV 和 ARV 对骨骼影响的人源化小鼠模型的表征

• 批准号: 10324198
• 负责人: Ryan Dee Ross
• 金额: $ 40.41万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-27 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324198
• 关键词: Address; Animal Model; Animals; Anti-Retroviral Agents; Automobile Driving; BLT mice; Bone Resorption; Bone Tissue; Bone remodeling; Cells; Chronic Disease; Clinical Trials; Complex; Confounding Factors (Epidemiology); Data; Development; Dual-Energy X-Ray Absorptiometry; Effectiveness; Epidemiology; Ethical Issues; Exposure to; Fetal Tissues; Fumarates; Goals; HIV; HIV Infections; HIV therapy; Histologic; Human; Infection; Lamivudine; Length; Link; Longevity; Mass Spectrum Analysis; Measures; Mediating; Modeling; Monitor; Mus; Osteoblasts; Osteocytes; Osteoporosis; Osteoporotic; Pathology; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Rattus; Regimen; Research Proposals; Risk; Rodent Model; Role; Sampling; Signal Pathway; Study models; Tenofovir; Testing; Time; Transgenic Organisms; Viral Proteins; abacavir; antiretroviral therapy; bone; bone cell; bone health; bone loss; bone mass; bone quality; bone strength; clinically relevant; comorbidity; cost effective; early onset; emtricitabine; experience; high reward; high risk; humanized mouse; in vivo; interest; irradiation; microCT; mouse model; negative affect; reconstitution; secondary endpoint; skeletal; tool; transcriptome sequencing

Project Summary / Abstract The development of highly effective antiretroviral (ARV) therapies has significantly increased the lifespan of people living with HIV (PLWH). Yet as HIV has become a chronic disease, it is becoming increasingly clear that PLWH have an increased risk for and an earlier onset of a variety of comorbidities, including osteoporosis. Our long-term goal is to identify the mechanism(s) of HIV and ARV-mediated bone loss. While human studies are highly valuable in defining phenomena and associations, they are complicated by sample accessibility, numerous confounding variables, and limitations in assessing cause and effect. Small animal models can be of value to probe the mechanism(s) implicated in HIV/ARV-induced bone loss. However, a critical barrier in the field is the difficulty in modeling HIV infection and ARV treatment in small animal models. Although several rodent models have been used to study the effects of HIV on bone, each has its own unique limitations. Therefore, in the current proposal we aim to characterize the NSG-HuPBMC mouse model to study the effects of HIV infection and ARV treatment on bone. The model has several key advantages: (1) it is relatively cost effective and less complex than other models, (2) allows for reconstitution and infection of cells of interest, and (3) there is no irradiation or fetal tissue required. The proposal will test the hypothesis that both HIV infection and ARV treatment induce loss of bone mass and reduced bone quality and strength in NSG-HuPBMC mice via two separate but independent aims that will determine the effects of HIV infection (Aim 1) and ARV treatment alone and in combination with HIV infection (Aim 2) on bone. The research proposal is well suited as a high risk/ high reward R21 application because assessing bone loss in this model can potentially establish it as a suitable model for studying HIV skeletal co-morbidities and most importantly define mechanisms that may inform the human condition.

项目概要/摘要 高效抗逆转录病毒（ARV）疗法的开发显着延长了患者的寿命 艾滋病毒感染者（PLWH）。然而，随着艾滋病毒已成为一种慢性疾病，这一点变得越来越清楚 PLWH 罹患各种合并症（包括骨质疏松症）的风险增加且发病较早。 我们的长期目标是确定 HIV 和 ARV 介导的骨质流失的机制。在人类研究的同时 在定义现象和关联方面非常有价值，它们因样本可访问性而变得复杂， 许多混杂变量以及评估因果关系的局限性。小动物模型可以是 探讨 HIV/ARV 引起的骨质流失的机制具有价值。然而，其中的一个关键障碍是 该领域的一个难题是在小动物模型中建立艾滋病毒感染和抗逆转录病毒治疗模型。虽然有几个 啮齿动物模型已被用来研究艾滋病毒对骨骼的影响，每种模型都有其独特的局限性。 因此，在当前的提案中，我们的目标是表征 NSG-HuPBMC 小鼠模型以研究其影响 HIV 感染和 ARV 治疗对骨骼的影响。该模型有几个关键优点：（1）相对成本 比其他模型有效且复杂性较低，(2) 允许重建和感染感兴趣的细胞，并且 (3)不需要辐射或胎儿组织。该提案将检验以下假设：HIV 感染 抗逆转录病毒治疗会导致 NSG-HuPBMC 小鼠骨量减少并降低骨质量和强度 通过两个独立但独立的目标来确定 HIV 感染（目标 1）和 ARV 的影响 单独治疗和与 HIV 感染（目标 2）联合治疗对骨骼的影响。该研究计划非常适合 高风险/高回报的 R21 应用，因为在此模型中评估骨丢失可能会确定它 作为研究 HIV 骨骼合并症的合适模型，最重要的是定义可能的机制 告知人类状况。