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.

项目摘要/摘要 联合抗逆转录病毒疗法(CART)的广泛使用显著延长了人的寿命 艾滋病毒携带者(PLWH)由于艾滋病毒已经成为一种慢性病，人们越来越关注 患多种合并症的风险不成比例。两种这样的合并症，在 CART治疗后的PLWH包括骨丢失和脂肪增加。有趣的是，由于新的治疗建议 改用骨骼毒性较小的CART疗法，似乎有更多的过度 增加脂肪和增加患代谢综合征的风险。我们的长期目标是确定 在CART治疗的PLWH中，导致这些并存情况的机制是为了找到更少的 有害的治疗选择。目前的提议将检验核心假设，即荷尔蒙 骨骼和脂肪之间的交流解释了抗逆转录病毒药物(ARV)如何导致骨骼丢失和脂肪增加 在PLWH。我们的假设是基于我们的初步数据，即荷尔蒙变化对抗逆转录病毒药物的反应 骨脂激素变化与BMD丢失和脂肪增加的相关性 入会仪式。为了验证我们的假设，我们建议采取一种分层方法，包括在体外， 临床前研究和人体研究。在目标1中，我们将定义单个抗逆转录病毒药物和购物车对 利用原代人类细胞实现骨和脂肪细胞的功能和荷尔蒙的产生。在目标2中，我们将调查 使用未感染的野生型小鼠对单个ARV和CART的骨骼和代谢反应 以及人类感染艾滋病毒的小鼠模型。最后，在目标3中，我们将确定 三个关键治疗阶段的骨和脂肪衍生激素以及骨量和身体成分，CART 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， 由早期研究人员(ESI)提交，将提供对以下疾病面临的关键并存的重要见解 Cart上的HIV患者-特别是通过说明单个ARV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，这项建议将增加我们对骨骼的总体了解- 脂肪荷尔蒙轴。