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.

项目总结/摘要 高效抗逆转录病毒（ARV）疗法的发展大大延长了 艾滋病毒感染者（PLWH）。然而，随着艾滋病毒成为一种慢性疾病， PLWH具有多种合并症的增加的风险和更早的发病，包括骨质疏松症。 我们的长期目标是确定HIV和ARV介导的骨丢失的机制。虽然人类研究 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复杂化， 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诱导骨丢失的机制。然而， 在小动物模型中建立HIV感染和ARV治疗的模型是该领域的难点。尽管几 啮齿动物模型已被用于研究HIV对骨骼的影响，每种模型都有其独特的局限性。 因此，在当前的提议中，我们的目标是表征NSG-HuPBMC小鼠模型以研究 艾滋病感染和抗逆转录病毒治疗的影响。该模型有几个关键的优点：（1）它是相对成本 有效且比其他模型更简单，（2）允许重建和感染感兴趣的细胞，和 (3)不需要辐射或胎儿组织。该提案将检验艾滋病毒感染者和艾滋病患者 和ARV治疗诱导NSG-HuPBMC小鼠中骨量丢失和骨质量和强度降低 通过两个单独但独立的目标，将确定艾滋病毒感染（目标1）和抗逆转录病毒药物的影响， 单独治疗和与HIV感染联合治疗（目的2）。该研究项目非常适合作为 高风险/高回报R21应用，因为在该模型中评估骨丢失可能会建立 作为研究HIV骨骼共病的合适模型，最重要的是定义可能 告知人类的状况。