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.

项目概要/摘要 联合抗逆转录病毒疗法（cART）的广泛使用显着延长了患者的寿命 艾滋病毒感染者（PLWH）。随着艾滋病毒成为一种慢性疾病，人们越来越关注 各种合并症的风险不成比例。两种此类合并症的发生率较高 cART 治疗的 PLWH 包括骨质流失和脂肪增加。有趣的是，随着新的治疗建议 转向骨毒性较小的 cART 治疗方案后，过量的患病率似乎有所增加 脂肪增加和代谢综合征发生的风险增加。我们的长期目标是确定 导致 cART 治疗的 PLWH 中这些共病的机制，以便发现更少的 有害的治疗选择。目前的提案将检验荷尔蒙的中心假设 骨骼和脂肪之间的沟通解释了抗逆转录病毒药物（ARV）如何导致骨质流失和脂肪增加 在艾滋病毒感染者中。我们的假设基于我们的初步数据，显示抗逆转录病毒药物引起的荷尔蒙变化 cART 治疗后骨和脂肪激素的变化与 BMD 减少和脂肪增加之间的相关性 引发。为了检验我们的假设，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，我们将定义个体 ARV 和 cART 对 使用原代人类细胞进行骨骼和脂肪细胞功能以及激素产生。在目标 2 中，我们将调查 使用未感染的野生型小鼠对个体 ARV 和 cART 的骨骼和代谢反应 以及艾滋病毒感染的人源化小鼠模型。最后，在目标 3 中，我们将确定之间的关联 三个关键治疗阶段的骨和脂肪源性激素以及骨量和身体成分，cART 启动、长期稳定的 cART 治疗以及转换 cART 方案。如果这项提议成功， 由早期研究者 (ESI) 提交，将为患者面临的主要合并症提供重要见解 接受 cART 治疗的 HIV 患者——特别是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 和荷尔蒙的产生。同时，这一提议将增加我们对骨骼的总体了解—— 脂肪荷尔蒙轴。