Brain exosome biomarker targets to optimize pharmacologic treatment of depression in pregnancy

脑外泌体生物标志物靶向优化妊娠期抑郁症的药物治疗

• 批准号: 10543638
• 负责人: Laura Goetzl
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543638
• 关键词: Affect; Antidepressive Agents; Binding Proteins; Biological Availability; Biological Markers; Blood; Brain; Clinical; Development; Dose; Evaluation; Fetus; Goals; Maternal Physiology; Mental Depression; Neonatal; Neonatal Abstinence Syndrome; Neuraxis; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology Study; Pharmacotherapy; Pilot Projects; Pregnancy; Pregnant Women; Public Health; Risk; Safety; Sampling; Selective Serotonin Reuptake Inhibitor; Source; Testing; Third Pregnancy Trimester; Withdrawal Symptom; Woman; antepartum depression; base; drug metabolism; effective therapy; evidence base; exosome; fetal; fetus at risk; improved; response; targeted biomarker; temporal measurement

This proposal aims to determine whether biomarkers in central nervous system-derived exosomes are useful predictors of functional drug activity in the maternal and fetal brain in women treated for depression during pregnancy with selective-serotonin reuptake inhibitors (SSRIs). PAR-20-299 specifically requests translational projects that will enhance the usage of existing drugs for safer and more effective treatment. Barriers to pharmacologic studies to optimize drug treatment in pregnant women include changes in maternal physiology, circulating binding proteins, biologically available drug levels, and drug metabolism. Real-time measurements of fetal drug levels are not currently feasible. Purification of CNSEs from maternal blood allows non- invasive independent evaluation of both the maternal and fetal CNS SSRI targets without significant contamination from each other or non-CNS sources. The goal of this pilot project is to develop a new testing paradigm to rapidly identify women who are poor responders to SSRIs and to investigate the relationship between SSRI treatment, exosome marker levels, and maternal clinical response at a steady state for a given SSRI dose. We will use fetal CNSEs isolated from the same maternal samples to determine if fetuses at risk for neonatal withdrawal symptoms can be identified prior to delivery. This would allow for improved evidence-based management of maternal SSRI treatment in the third trimester based on individualized fetal/neonatal risk and ultimately has the potential to avoid unnecessary medication discontinuation. Completion of this project can change the paradigm for how we assess the safety and efficacy of psychoactive medications in pregnancy.

该提案旨在确定中枢神经系统来源的生物标志物是否 外泌体是女性母体和胎儿脑中功能性药物活性的有用预测因子 在怀孕期间用选择性5-羟色胺再摄取抑制剂（SSRIs）治疗抑郁症。 PAR-20-299特别要求翻译项目，将加强现有的 更安全、更有效的治疗方法。优化药物的药理学研究的障碍 孕妇的治疗包括改变母体生理学、循环结合 蛋白质、生物可利用的药物水平和药物代谢。实时测量胎儿 药物水平目前尚不可行。从母体血液中纯化CNSE允许非- 母体和胎儿CNS SSRI靶点的侵入性独立评估， 来自彼此或非CNS来源的显著污染。该试点项目的目标是 开发一种新的测试模式，以快速识别对SSRIs反应不良的妇女， 研究SSRI治疗、外泌体标记物水平和母体妊娠之间的关系， 对于给定的SSRI剂量，稳态下的临床应答。我们将使用胎儿CNSE分离， 使用相同的母体样本来确定有新生儿戒断症状风险的胎儿是否可以 在交付之前确认。这将有助于改善对儿童的循证管理， 基于个体化胎儿/新生儿风险的妊娠晚期母体SSRI治疗， 最终有可能避免不必要的停药。完成本 该项目可以改变我们如何评估精神活性药物的安全性和有效性的范式。 怀孕期间的药物