Identifying the long-term metabolic complications of in-utero and lactational antiretroviral exposure

确定子宫内和哺乳期抗逆转录病毒暴露的长期代谢并发症

• 批准号: 10762179
• 负责人: Ryan Dee Ross
• 金额: $ 15.8万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-06 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762179
• 关键词: Address; Adipocytes; Adult; Aftercare; Age; Age-Related Bone Loss; Aging; Anti-Retroviral Agents; Automobile Driving; Bone Banks; Bone Density; Bone Development; Bone structure; Breast Feeding; Child; Clinical; Data; Data Set; Development; Discipline of Nursing; Experimental Designs; Exposure to; Extracellular Matrix; Fatty acid glycerol esters; Female; Gene Expression; Genes; Goals; HIV; Human; Impairment; In Vitro; Inflammatory; Knowledge; Lactation; Lamivudine; Long-Term Effects; Longevity; Mechanics; Metabolic; Mothers; Neurologic Examination; Nucleosides; Obesity; Osteoporosis; Perinatal transmission; Persons; Population; Pregnancy; Pregnant Women; Rattus; Recommendation; Research; Research Design; Reverse Transcriptase Inhibitors; Risk; Risk Factors; Sampling; Signal Transduction; Skeletal Development; Spectrum Analysis; Testing; Tissues; Vertebral column; Visceral; Vulnerable Populations; Weight Gain; Western Blotting; Withholding Treatment; Woman; World Health Organization; abacavir; adiponectin; aged; antiretroviral therapy; bone; bone aging; bone loss; bone mass; bone quality; bone strength; cardiovascular disorder risk; cytokine; design; emerging adult; experimental study; in utero; innovation; lipid metabolism; male; microCT; model organism; osteoporosis with pathological fracture; perinatal HIV; postnatal; prenatal therapy; prevent; secondary analysis; skeletal; transmission process

Project Summary / Abstract The increased use of combination antiretroviral therapy (cART) has significantly reduced the perinatal transmission of HIV. However, as more HIV-infected women take cART, there is an increasing population of children exposed to cART in-utero and while nursing. The World Health Organization (WHO) now recommends dolutegravir (DTG)-based cART as first-line treatment for all people living with HIV, including pregnant women. Although early exposure to non-DTG based cART has been associated with bone and fat-related complications, the long-term consequences of in-utero and lactational exposure to DTG are completely unknown and will take decades to determine. The current proposal aims to address this gap in knowledge by leveraging banked bone and fat samples from an 18-month rat experiment to test the hypothesis that developmental exposure to DTG-based cART will cause lasting deleterious effects on bone and fat tissues. To test this hypothesis, we will determine the effects of in-utero and lactational exposure to DTG-based cART on (1) bone mass and quality using micro-computed tomography, Raman microspectroscopy, and mechanical testing and (2) fat tissue using RNAsequencing, RT-qPCR, and western blot analysis. The current proposal is significant because it addresses a critical clinical concern. The research question is timely, as DTG-based cART has become the recommended first line cART for all people living with HIV, including pregnant women. The hypothesis is conceptually innovative, as the metabolic consequences of early DTG exposure are unknown. Finally, the proposed aims are well-matched to the R03 programmatic goals as they represent a secondary analysis of an existing dataset. Results from this proposal will begin to establish the long-term effects of developmental exposure to DTG on bone and fat tissues and begin to determine the driving mechanisms.

项目总结/摘要 联合抗逆转录病毒疗法（cART）的使用增加， 艾滋病毒的传播。然而，随着越来越多的艾滋病毒感染妇女接受cART， 宫内和哺乳期暴露于cART的儿童。世界卫生组织（WHO）建议 基于dolutegravir（DTG）的cART作为所有艾滋病毒感染者（包括孕妇）的一线治疗。 尽管早期暴露于非DTG基础的cART与骨和脂肪相关的 并发症，子宫内和哺乳期暴露于DTG的长期后果完全 未知，需要几十年才能确定。目前的建议旨在填补这一知识空白 通过利用18个月大鼠实验中储存的骨骼和脂肪样本来验证这一假设， 发育暴露于基于DTG的cART将对骨和脂肪组织造成持久的有害影响。到 为了验证这一假设，我们将确定子宫内和哺乳期暴露于基于DTG的cART对 (1)骨质量和质量使用微计算机断层扫描，拉曼显微光谱，和机械 使用RNA测序、RT-qPCR和蛋白质印迹分析检测和（2）脂肪组织。当前的提议是 因为它解决了一个关键的临床问题。研究问题是及时的，因为DTG是基于 cART已成为所有艾滋病毒感染者（包括孕妇）的推荐一线cART。 这一假设在概念上是创新的，因为早期DTG暴露的代谢后果是 未知最后，建议的目标与R 03计划目标非常匹配，因为它们代表了 对现有数据集进行二次分析。该提案的结果将开始建立长期 发育暴露于DTG对骨骼和脂肪组织的影响，并开始确定驾驶 机制等