Investigation of acute and long-term neuroimmune changes induced by early-life opioid exposure and withdrawal

项目摘要/摘要 在美国所有人口中，阿片类药物的使用急剧增加，包括怀孕 女人。怀孕期间阿片类药物使用量的增加会导致婴儿的健康问题，他们可能会患上急性 出生后不久出现阿片类药物戒断症状，导致新生儿阿片类药物戒断 综合征(NOWS)。NOWS的治疗没有标准，尽管一些医院选择使用 吗啡减量或丁丙诺啡。尽管诊断率不断上升，但NOWS对 细胞功能、生理发育和行为尚未完全确定。阿片类药物 免疫系统的调节剂，并在中枢神经系统内发挥促炎作用，通过 与小胶质细胞结合。临床数据显示，被诊断为NOWS的婴儿可能存在免疫功能障碍， 但这些研究是有限的，结果还没有在临床前模型中得到充分检验。用一本小说 在NOWS小鼠模型(“三个月模型”)中，我们发现了小胶质细胞水平增加的证据 在戒断后立即由围产期阿片类药物暴露所致。这种神经免疫的全部范围 功能障碍，以及长期的变化，还有待研究。这项提议的目标是充分 描述早期阿片类药物暴露引起的急性和持续性神经免疫变化 并评价小胶质细胞作为缓解戒断症状的潜在治疗靶点。目标 1将研究出生后立即停用阿片类药物后小胶质细胞和细胞因子的急性变化。 第15天：目标2将测量成年期持续的神经免疫改变，包括基线和反应 通过检查分子变化和疾病反应行为来应对免疫挑战。目标3将 药物抑制小胶质细胞的激活并评估戒断症状的改善。 这些目标的成功完成将充分表征围产期阿片类药物引起的神经免疫变化 暴露和戒断，并为治疗NOWS的新治疗靶点提供证据。通过这件事 作为奖学金，Ferrante女士将完成确定的培训目标，包括分子技术熟练程度 实验室技术，神经免疫学领域的专业知识，精致的书面和口头科学 交流，专业发展，走向学术研究的职业生涯。这一团契还将 促进在实现其当前和未来研究目标方面取得进展，以便能够取得成功 独立研究人员。

Project Summary/Abstract Opioid use has increased drastically among all demographics in the United States, including in pregnant women. This rise opioid use during pregnancy leads to health concerns for infants, who may develop acute opioid withdrawal symptoms shortly after birth, resulting in a diagnosis of Neonatal Opioid Withdrawal Syndrome (NOWS). There is no standard of treatment for NOWS, though some hospitals choose to treat using morphine tapering or buprenorphine. Despite increasing rates of diagnoses, the long-term effects of NOWS on cellular function, physiological development, and behavior have yet to be fully characterized. Opioids are modulators of the immune system and exert pro-inflammatory effects within the central nervous system by binding to microglia. Clinical data has shown potential immune dysfunction in infants diagnosed with NOWS, but these studies are limited, and results have not yet been fully examined in preclinical models. Using a novel mouse model of NOWS (“the three-trimester model”), we have found evidence of increased microglia levels induced by perinatal opioid exposure immediately after withdrawal. The full extent of this neuroimmune dysfunction, as well as the long-term changes, have yet to be studied. The goal of this proposal is to fully characterize the acute and persisting neuroimmune changes induced by early life opioid exposure and withdrawal, and to evaluate microglia as a potential therapeutic target in mitigating withdrawal symptoms. Aim 1 will investigate acute changes in microglia and cytokines immediately following opioid withdrawal at postnatal day 15. Aim 2 will measure persisting neuroimmune alterations in adulthood, both at baseline and in response to an immune challenge, by examining molecular changes and sickness response behavior. Aim 3 will pharmacologically suppress microglial activation and assess for improvements in withdrawal symptoms. Successful completion of these aims will fully characterize neuroimmune changes induced by perinatal opioid exposure and withdrawal and provide evidence for a novel therapeutic target in treating NOWS. Through this fellowship, Ms. Ferrante will accomplish defined Training Goals, including technical proficiency in molecular laboratory techniques, expertise in the field of neuroimmunology, refined written and oral scientific communication, and professional development towards a career in academic research. This fellowship will also facilitate progress towards achieving her current and future research goals in order to enable success as an independent researcher.