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 组合抗逆转录病毒疗法（CART）的广泛使用已显着提高了 患有艾滋病毒（PLWH）的人。随着艾滋病毒已成为一种慢性疾病，人们对 多种合并症的风险不成比例。两种此类合并症发生在较高的患病率 手推车处理的PLWH包括骨质流失和脂肪增加。有趣的是，随着新的治疗建议 转移到骨有毒较小的购物车方案，似乎有多余的患病率 脂肪增益和代谢综合征发展的风险增加。我们的长期目标是确定 为了发现较少的货车处理的PLWH的机制，导致这些合并症 有害的治疗选择。当前的提议将测试马的中心假设 骨骼和脂肪之间的通信解释了抗逆转录病毒（ARV）如何促进骨质流失和脂肪增加 在PLWH中。我们的假设是基于我们的初步数据，显示了响应ARV的激素变化 骨骼和脂肪恐怖的变化与BMD损失与脂肪增加与购物车之间的相关性 引发。为了检验我们的假设，我们建议采用一种层次方法，其中将包括体外， 临床前和人类学科研究。在AIM 1中，我们将定义单个ARV和推车对 骨和脂肪细胞功能和使用原代人细胞产生的骨骼功能。在AIM 2中，我们将调查 使用未感染的野生型小鼠对单个ARV的骨骼和代谢反应 和人源化的HIV感染模型。最后，在AIM 3中，我们将确定 在三个关键治疗阶段，骨骼和脂肪衍生的恐怖片以及骨骼质量和身体成分，购物车 启动，长期稳定的购物车治疗和切换手推车方案。如果成功，这个建议， 由早期调查员（ESI）提交的，将提供有关关键合并症的重大见解 手推车上的HIV患者 - 特别是通过阐明单个ARV对骨/脂肪细胞功能的负面影响 和马匹生产。同时，该提议将增加我们对骨骼的一般理解 脂肪马轴。