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.

项目摘要 /摘要 高效抗逆转录病毒（ARV）疗法的发展显着提高了 患有艾滋病毒（PLWH）的人。然而，随着艾滋病毒已成为一种慢性疾病，它变得越来越清楚 该PLWH的风险增加，并且早期发作多种合并症，包括骨质疏松症。 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，样本可访问性使它们复杂化， 许多混淆变量以及评估因果的局限性。小动物模型可以是 探测与HIV/ARV诱导的骨质流失有关的机制的价值。但是，在 在小动物模型中，领域是建模HIV感染和ARV治疗的困难。虽然有几个 啮齿动物模型已用于研究艾滋病毒对骨骼的影响，每种都有其独特的局限性。 因此，在当前的建议中，我们旨在表征NSG-HUPBMC小鼠模型以研究效果 HIV感染和ARV治疗的骨骼。该模型具有多个关键优势：（1）相对成本 有效且比其他模型不那么复杂，（2）允许重新建立和感染感兴趣的细胞，并且 （3）不需要辐照或胎儿组织。该提案将检验两种HIV感染的假设 NSG-HUPBMC小鼠的骨骼质量和骨质质量和强度降低会导致骨骼质量损失 通过两个独立但独立的目标，这些目标将决定艾滋病毒感染的影响（AIM 1）和ARV 单独治疗并与HIV感染（AIM 2）在骨骼上进行治疗。研究建议非常适合 高风险/高奖励R21应用程序，因为评估该模型中的骨质流失可以可能建立 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。