Bone and fat cross-talk in antiretroviral therapy (ART) treated HIV patients

抗逆转录病毒疗法 (ART) 治疗的 HIV 患者的骨和脂肪交叉对话

• 批准号: 10548410
• 负责人: Ryan Dee Ross
• 金额: $ 41.78万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548410
• 关键词: AIDS clinical trial group; Adipocytes; Affect; Animal Model; Anti-Retroviral Agents; Biological; Biological Markers; Body Composition; Cell Communication; Cell Culture Techniques; Cell physiology; Cells; Chronic Disease; Clinical; Cohort Studies; Communication; Confounding Factors (Epidemiology); Data; Development; Dual-Energy X-Ray Absorptiometry; Effectiveness; Face; Fatty acid glycerol esters; Fumarates; Goals; HIV; HIV Infections; HIV antiretroviral; Head; High Prevalence; Hormonal; Hormonal Change; Hormones; Human; In Vitro; Individual; Insulin; Insulin Resistance; Integrase; Knowledge; Leptin; Longevity; Measures; Metabolic; Metabolic syndrome; Nucleosides; Nucleotides; Osteoblasts; Osteocalcin; Osteoporosis; Patients; Persons; Pharmaceutical Preparations; Plasma; Prevalence; Production; Protease Inhibitor; Recommendation; Regimen; Research Personnel; Reverse Transcriptase Inhibitors; Risk; Ritonavir; Role; Sampling; Stimulus; Study Subject; Tenofovir; Testing; Time; Tissues; Triglycerides; Weight; Wild Type Mouse; adipocyte differentiation; adiponectin; antiretroviral therapy; base; bone; bone cell; bone loss; bone mass; comorbidity; defined contribution; experimental study; human subject; humanized mouse; improved; inhibitor; insight; mouse model; negative affect; novel; novel therapeutics; pre-clinical; response; skeletal

Project Summary / Abstract The widespread use of combination antiretroviral therapy (cART) has significantly increased the lifespan of people living with HIV (PLWH). As HIV has become a chronic disease, there is a growing concern of the disproportionate risk of a variety of comorbidities. Two such comorbidities that occur at a higher prevalence in cART treated PLWH include bone loss and fat gain. Interestingly, as new treatment recommendations have shifted to cART regimens that are less bone toxic, there appears to be an increased prevalence of excessive fat gain and an increased risk for the development of metabolic syndrome. Our long-term goal is to determine the mechanisms contributing to these comorbid conditions in cART treated PLWH in order to find less deleterious treatment options. The current proposal will test the central hypothesis that the hormonal communication between bone and fat explains how antiretrovirals (ARVs) contribute to bone loss and fat gain in PLWH. Our hypothesis is based on our preliminary data showing hormonal changes in response to ARVs and correlations between the changes in bone and fat hormones and BMD loss and fat gain with cART initiation. To test our hypothesis, we propose to take a hierarchical approach that will include in vitro, preclinical, and human subject studies. In Aim 1, we will define the contribution of individual ARVs and cART to bone and fat cellular function and hormonal production using primary human cells. In Aim 2, we will investigate the skeletal and metabolic response to individual ARVs and cART using both an uninfected wild-type mouse and a humanized mouse model of HIV-infection. Finally, in Aim 3, we will determine the association between bone and fat-derived hormones and bone mass and body composition in three critical treatment stages, cART initiation, long-term stable cART treatment, and switching cART regimens. If successful, this proposal, submitted by an early stage investigator (ESI), will provide significant insights into key comorbidities faced by HIV patients on cART—specifically by illuminating how individual ARVs negatively affect bone/fat cell function and hormonal production. At the same time, this proposal will increase our general understanding of the bone- fat hormonal axis.

项目总结/摘要 联合抗逆转录病毒疗法（cART）的广泛使用显著增加了 艾滋病毒感染者（PLWH）。由于艾滋病毒已成为一种慢性疾病， 多种合并症的不成比例风险。两种这样的合并症，发生率较高， cART治疗的PLWH包括骨丢失和脂肪增加。有趣的是，随着新的治疗建议 转移到骨毒性较低的cART方案，似乎有过度的患病率增加 脂肪增加和代谢综合征风险增加。我们的长期目标是确定 在接受cART治疗的PLWH中导致这些共病状况的机制， 有害的治疗选择。目前的建议将测试中心假设，即激素 骨和脂肪之间的沟通解释了抗逆转录病毒药物（ARV）如何导致骨丢失和脂肪增加 在PLWH。我们的假设是基于我们的初步数据显示激素变化的反应，抗逆转录病毒药物 以及骨和脂肪激素变化与骨密度降低和脂肪增加与cART的相关性 初始化。为了验证我们的假设，我们建议采取分层方法，包括体外， 临床前和人类受试者研究。在目标1中，我们将定义单个抗逆转录病毒药物和cART对 骨和脂肪细胞功能以及使用原代人类细胞产生激素。在目标2中，我们将研究 使用未感染的野生型小鼠， 和HIV感染的人源化小鼠模型。最后，在目标3中，我们将确定 在三个关键治疗阶段，cART中的骨和脂肪源性激素以及骨量和身体成分 启动、长期稳定的cART治疗和转换cART方案。如果成功的话，这个提议， 由早期研究者（ESI）提交，将为以下患者面临的关键合并症提供重要见解： 通过阐明个体抗逆转录病毒药物如何对骨/脂肪细胞功能产生负面影响， 和荷尔蒙分泌与此同时，这一提议将增加我们对骨骼的总体了解- 脂肪激素轴