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.

该建议旨在确定中枢神经系统衍生的生物标志物是否 外泌体是女性孕产妇和胎儿大脑功能性药物活性的有用预测指标 通过选择性 - 羟基再摄取抑制剂（SSRIS）治疗怀孕期间的抑郁症。 PAR-20-299专门要求转化项目，以增强现有的使用 用于更安全，更有效治疗的药物。优化药物的药理研究障碍 孕妇的治疗包括孕产妇生理的变化，循环结合 蛋白质，生物可用的药物水平和药物代谢。胎儿的实时测量 药物水平目前不可行。从母血中纯化中枢神经系统允许非 侵入性的独立评估母体和胎儿中枢神经系统SSRI目标 彼此或非CNS来源的显着污染。该试点项目的目标是 开发一个新的测试范式，以迅速识别妇女对SSRI和SSRI和 研究SSRI处理，外泌体标记水平和母体之间的关系 给定SSRI剂量的稳定态临床反应。我们将使用与隔离的胎儿中枢神经系统 相同的母亲样本以确定有新生儿戒断症状风险的胎儿是否可以 在交货前确定。这将允许改进基于证据的管理 基于个性化的胎儿/新生儿风险和 最终有可能避免不必要的药物停用。完成此操作 项目可以改变范式，以评估精神活性的安全性和功效 怀孕的药物。