Altered postnatal microglial function following fetal inflammation and its effect on long-term neurodevelopment of neonatal mice

摘要：母体绒毛膜炎是妊娠<28周分娩的最常见原因， 胎儿出现严重的免疫反应，称为“胎儿炎症反应综合征”（FIRS）。一个主要 FIRS早产儿的后果是长期神经发育障碍的风险更高 与无FIRS的早产儿相比。脑损伤可能是由于FIRS诱导的产前激活 小胶质细胞，中枢神经系统的常驻免疫细胞。激活的小胶质细胞有助于脑损伤 至少有两个重要的原因：1）急性产前功能变化损伤脑细胞并转移小胶质细胞 2）出生后功能的改变导致小胶质细胞对出生后发育任务的异常反应。 炎症事件。该建议的中心假设是，针对FIRS的治疗策略- 产前小胶质细胞激活或产后炎症反应的诱导机制将阻止或 解决小胶质细胞功能异常并改善神经发育结果。研究目的 是：1）阐明特定的FIRS诱导的小胶质细胞激活机制，利用遗传抑制， 定时离体治疗干预方法和2）测试是否抑制产前小胶质细胞 激活或体内出生后小胶质细胞应答将使小胶质细胞功能正常化并防止异常的 长期的神经发育。目的将通过使用FIRS小鼠模型和出生后研究进行评价 小胶质细胞的功能和长期的神经发育结果。所获得的知识预计将 导致开发用于受FIRS影响的早产儿的治疗剂，并广泛适用于 其他新生儿脑损伤，包括缺氧缺血性脑病和中风。研究和职业生涯 提出的发展计划将共同促进追求候选人的长期目标：1）成为 一个独立资助的实验室为基础的研究领域的新生儿神经免疫学和 神经发育，2）将动物模型结果转化为新生儿临床研究，3）传播 国内/国际研究结果，以便对新生儿实践产生影响，以及4）成为 教师指导学生和各级学员。长期目标将在以下方面的帮助下实现： 在实验室和课堂上进行结构化的指导和学习，以实现直接目标： 提高研究和演示技能，免疫学和神经科学知识， 学生辅导选择候选人的共同导师是为了最大限度地发挥他们在以下方面的优势： 研究项目和职业发展计划。James Lokensgard博士是一位神经炎症专家， 科学技术和对小神经胶质细胞的研究符合这项建议的目标。Michael Georgieff博士是一位 神经发育和临床前模型方面的专家，以评估生命早期对大脑的影响。统称 明尼苏达大学通过学术健康中心和 儿科确保成功完成拟定研究。

ABSTRACT: Maternal chorioamnionitis, the most common cause of birth <28 weeks gestation, initiates a severe, immune reaction in the fetus known as the “Fetal Inflammatory Response Syndrome” (FIRS). A major consequence for preterm infants with FIRS is a much higher risk of long-term neurodevelopmental disability compared to preterm infants without FIRS. Brain injury likely occurs due to FIRS-induced prenatal activation of microglia, the resident immune cell of the central nervous system. Activated microglia contribute to brain injury for at least two important reasons: 1) Acute prenatal functional changes injure brain cells and divert microglia from developmental tasks and 2) Altered postnatal function causes abnormal microglial response to postnatal inflammatory events. The central hypothesis of this proposal is that therapeutic strategies targeting FIRS- induced mechanisms of prenatal microglial activation or postnatal inflammatory responses will prevent or resolve microglial functional abnormalities and improve neurodevelopmental outcomes. The aims of the study are: 1) to elucidate specific FIRS-induced mechanisms of microglial activation utilizing genetic inhibition and timed ex vivo therapeutic intervention approaches and 2) to test whether inhibition of prenatal microglial activation or in vivo postnatal microglial responses will normalize microglial function and prevent abnormal long-term neurodevelopment. The aims will be evaluated by using a murine model of FIRS and postnatal study of microglial function and long-term neurodevelopmental outcomes. The knowledge gained is anticipated to lead to the development of therapeutics for preterm infants affected by FIRS and to be broadly applicable to other neonatal brain injuries, including hypoxic-ischemic encephalopathy and stroke. The research and career development plans proposed will jointly facilitate the pursuit of the candidate’s long-term goals: 1) to become an independently-funded laboratory-based investigator in the fields of neonatal neuroimmunology and neurodevelopment, 2) to translate animal model findings to neonatal clinical studies, 3) to disseminate research findings nationally/internationally in order to make an impact on neonatal practice, and 4) to be a faculty mentor to students and trainees at all levels. The long-term goals will be achieved with the aid of structured mentoring and learning in the laboratory and classroom that will address immediate goals: to improve research and presentation skills, immunology and neuroscience knowledge, grantsmanship, and student mentoring. The candidate’s co-mentors were chosen to maximize their strengths related to the research project and career development plan. Dr. James Lokensgard is a neuroinflammation expert whose scientific techniques and studies of microglia match with the aims of this proposal. Dr. Michael Georgieff is an expert in neurodevelopment and preclinical models to assess early life effects on the brain. Collectively, the University of Minnesota’s commitment to the candidate through both the Academic Health Center and the Department of Pediatrics ensures the successful completion of the proposed studies.