The Contribution of Sleep and Circadian Disruption to Kynurenine Pathway Activation and Cardiometabolic Risk in Women with HIV

睡眠和昼夜节律紊乱对艾滋病毒女性犬尿氨酸通路激活和心脏代谢风险的影响

• 批准号: 10162654
• 负责人: Helen Julia Burgess
• 金额: $ 46.28万
• 依托单位: HEKTOEN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162654
• 关键词: Anti-Inflammatory Agents; Atherosclerosis; Back; Cardiometabolic Disease; Chronic; Circadian Dysregulation; Cognitive Therapy; Cohort Studies; Data; Enzymes; Foundations; HIV; HIV Infections; HIV tat Protein; HIV therapy; High Prevalence; Individual; Inflammation; Inflammatory; Intervention; Kynurenine; Link; Longitudinal Studies; Mediating; Melatonin; Molecular; Morbidity - disease rate; Pathway interactions; Phototherapy; Pilot Projects; Property; Research; Research Design; Risk; Risk Marker; Site; Sleep; Sleep disturbances; Sleeplessness; Symptoms; Testing; Time; Tryptophan; Tryptophan 2,3 Dioxygenase; Woman; Women' s Interagency HIV Study; antiretroviral therapy; cardiometabolic risk; cardiometabolism; circadian; circadian regulation; cohort; comorbidity; disorder risk; immune activation; insight; melatonin supplementation; mortality; multidisciplinary; novel; older women

ABSTRACT Immune activation and inflammation persist despite combination antiretroviral therapy (cART) for HIV. This chronic inflammation contributes to greater HIV-associated cardiometabolic morbidity and mortality. Our group recently found that a specific molecular mechanism - the tryptophan-kynurenine (TRP-KYN) pathway - is disrupted in HIV and associated with atherosclerosis progression. The TRP-KYN pathway is of potential importance in both HIV and sleep/circadian regulation because HIV Tat protein and inflammatory molecules induce TRP-KYN pathway activation, which results in a degradation of TRP, an imbalance and accumulation of KYN and its downstream metabolites, and a reduction in melatonin, which is a circadian regulator with anti- inflammatory properties. Sleep and circadian disruption are highly prevalent in HIV, and sleep and circadian disruption are well-recognized to increase inflammation. Therefore, sleep and circadian disruption may further activate the TRP-KYN pathway, increasing HIV-associated cardiometabolic disease risk. The objective of this application is to investigate the TRP-KYN pathway as a molecular mechanism by which sleep and circadian disruption increase risk for HIV-associated cardiometabolic disease. We will also investigate the reciprocal relationship by which HIV-related TRP-KYN pathway activation may feed back to increase sleep and circadian disruption. Our multidisciplinary team will leverage the ongoing multi-site Women's Interagency HIV Study (WIHS) cohort of well-characterized HIV+ and demographically similar HIV- women, which has extensive cardiometabolic data. Our pilot data from WIHS indicate that (1) sleep and circadian disruption is prevalent in the WIHS cohort, (2) sleep and circadian disruption can potentiate immune activation, particularly in HIV- infected individuals, and (3) TRP-KYN pathway activation increases risk for cardiometabolic disease. Thus, we will study 240 women (120 HIV+ aviremic, 120 HIV-, 40-70 y) in a longitudinal study design, assessing sleep and circadian disruption, TRP-KYN pathway activation and cardiometabolic risk yearly over 2 years (3 time points). Aim 1 is to determine the degree to which sleep and circadian disruption are associated with, and can predict, TRP-KYN pathway activation in HIV+ women. Aim 2 is to determine the degree to which sleep and circadian disruption are associated with, and can predict, HIV-associated cardiometabolic disease risk. Aim 3 is to determine whether the TRP-KYN pathway is a mechanism that links sleep and circadian disruption to an increase in HIV-associated cardiometabolic disease risk. No studies to date have examined TRP-KYN pathway activation and its metabolites as a mechanism linking sleep/circadian disruption to HIV-related comorbidities such as cardiometabolic disease. Results will provide novel insights into the mechanistic relationships between sleep and circadian disruption, TRP-KYN pathway activation, and HIV-associated cardiometabolic disease risk and provide a strong foundation upon which to test targeted sleep and circadian interventions to reduce risk for cardiometabolic disease in women with HIV.

摘要 尽管联合抗逆转录病毒疗法（cART）治疗HIV，免疫激活和炎症仍然存在。这 慢性炎症导致更高的HIV相关心脏代谢发病率和死亡率。我们集团 最近发现一种特定的分子机制--色氨酸-犬尿氨酸（TRP-KYN）途径--是 在HIV中被破坏并与动脉粥样硬化进展相关。TRP-KYN通路具有潜在的 由于HIV达特蛋白和炎症分子 诱导TRP-KYN途径活化，其导致TRP降解、 KYN及其下游代谢物，以及褪黑激素的减少，褪黑激素是一种具有抗 炎症特性。睡眠和昼夜节律紊乱在艾滋病患者中非常普遍， 破坏被公认会增加炎症。因此，睡眠和昼夜节律紊乱可能会进一步 激活TRP-KYN通路，增加HIV相关心脏代谢疾病风险。的目的 应用程序是研究TRP-KYN通路作为睡眠和昼夜节律的分子机制， 中断会增加HIV相关心脏代谢疾病风险。我们还将研究互惠 HIV相关TRP-KYN通路激活可能反馈增加睡眠和昼夜节律的关系 破坏我们的多学科团队将利用正在进行的多地点妇女机构间艾滋病毒研究 （WIHS）特征明确的艾滋病毒阳性和人口统计学上相似的艾滋病毒阴性妇女队列， 心脏代谢数据。我们来自WIHS的试点数据表明，（1）睡眠和昼夜节律紊乱在老年人中普遍存在， （2）睡眠和昼夜节律紊乱可增强免疫激活，特别是在HIV- 感染的个体，和（3）TRP-KYN途径激活增加心脏代谢疾病的风险。因此我们 将在一项纵向研究设计中研究240名妇女（120名HIV+病毒血症，120名HIV-，40-70岁），评估睡眠 和昼夜节律紊乱，TRP-KYN通路激活和心脏代谢风险，每年超过2年（3次 点）。目的1是确定睡眠和昼夜节律紊乱的相关程度， 预测HIV阳性女性中TRP-KYN通路的激活。目标2是确定睡眠和 昼夜节律紊乱与HIV相关的心脏代谢疾病风险相关，并可预测HIV相关的心脏代谢疾病风险。目标3 是为了确定TRP-KYN通路是否是一种机制，将睡眠和昼夜节律中断与一种神经系统疾病联系起来。 艾滋病毒相关心脏代谢疾病风险增加。到目前为止，还没有研究检查TRP-KYN通路 激活及其代谢物作为睡眠/昼夜节律紊乱与HIV相关合并症的联系机制 例如心脏代谢疾病。结果将提供新的见解之间的机械关系 睡眠和昼夜节律紊乱、TRP-KYN通路激活和HIV相关心脏代谢疾病风险 并为测试有针对性的睡眠和昼夜节律干预措施以降低 艾滋病毒感染妇女的心脏代谢疾病。

项目成果

Overnight urinary melatonin levels in women with and without HIV: An observational cohort study.

• DOI: 10.1002/brb3.3206
• 发表时间: 2023-10
• 期刊: BRAIN AND BEHAVIOR
• 影响因子: 3.1
• 作者: Burgess, Helen J. J.;Weber, Kathleen M. M.;Morack, Ralph;Yohannes, Tsion;Xing, Jiaqian;Xue, Xiaonan;Gustafson, Deborah;Sharma, Anjali;Daubert, Elizabeth;Rogando, Andrea C. C.;French, Audrey L. L.
• 通讯作者: French, Audrey L. L.