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

胎儿炎症后出生后小胶质细胞功能的改变及其对新生小鼠长期神经发育的影响

• 批准号: 10214654
• 负责人: Tate A. Gisslen
• 金额: $ 13.57万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-09 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214654
• 关键词: Ablation; Accounting; Acute; Address; Adult; Affect; Age; Amniotic Fluid; Animal Model; Antigens; Birth; Brain; Brain Injuries; Cells; Clinical Research; Data; Development; Development Plans; Disease; Endothelium; Ensure; Event; Exposure to; Fetus; Funding; Genetic; Goals; Health; Histone Acetylation; Immune; Immunology; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-6; International; Intervention; Investigation; Ischemic Stroke; Knowledge; Laboratories; Lead; Learning; Life; Literature; Meningitis; Mentors; Microbe; Microglia; Minnesota; Modeling; Neonatal; Neonatal Brain Injury; Neuraxis; Neurodevelopmental Disability; Neurological outcome; Neurons; Neurosciences; Outcome; Pathway interactions; Pharmacology; Phenotype; Physicians; Placenta; Pre-Clinical Model; Pregnancy; Premature Birth; Premature Infant; Research; Research Personnel; Research Project Grants; Research Training; Risk; Role; Scientist; Sepsis; Signal Pathway; Structure; Students; Techniques; Testing; Therapeutic; Therapeutic Intervention; Training; Translating; Universities; base; behavior test; brain cell; career development; critical period; cytokine; design; experience; experimental study; faculty mentor; fetal; fetal inflammatory response syndrome; high risk; immunoreaction; improved; in vivo; in vivo Model; innovation; intraamniotic infection; mortality; mouse model; neonatal hypoxic-ischemic brain injury; neonatal mice; neonatal morbidity; neurodevelopment; neuroimmunology; neuroinflammation; neuron development; pathogen; pediatric department; postnatal; prenatal; prevent; programs; receptor; research and development; response; skills; student mentoring; synaptogenesis; targeted agent; therapeutic development; tool development

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.

摘要：孕产妇绒毛膜羊膜炎是妊娠 28 周以下最常见的出生原因，引发了 胎儿发生严重的免疫反应，称为“胎儿炎症反应综合征”(FIRS)。 患有 FIRS 的早产儿的后果是长期神经发育障碍的风险更高 与没有 FIRS 的早产儿相比，脑损伤可能是由于 FIRS 诱导的产前激活所致。 小胶质细胞是中枢神经系统的常驻免疫细胞，激活的小胶质细胞会导致脑损伤。 至少有两个重要原因：1）急性产前功能变化会损伤脑细胞并转移小胶质细胞 发育任务和 2) 产后功能改变导致小胶质细胞对产后反应异常 该提案的中心假设是针对 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预防或 解决小胶质细胞功能异常并改善神经发育结果该研究的目的。 是：1）利用遗传抑制和机制来阐明 FIRS 诱导的小胶质细胞激活的特定机制 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反应将使小胶质细胞功能正常化并防止异常 长期神经发育目标将通过使用 FIRS 小鼠模型和产后研究进行评估。 预计所获得的知识将有助于了解小胶质细胞功能和长期神经发育结果。 导致针对受 FIRS 影响的早产儿的治疗方法的开发，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的研究和职业。 提出的发展计划将共同促进候选人实现长期目标：1）成为 新生儿神经免疫学领域独立资助的实验室研究人员 神经发育，2) 将动物模型研究结果转化为新生儿临床研究，3) 传播 国家/国际研究成果，以便对新生儿实践产生影响，以及 4) 成为 各级学生和学员的教师导师将在以下人员的帮助下实现。 在实验室和课堂上进行结构化指导和学习，以实现近期目标： 提高研究和演讲技巧、免疫学和神经科学知识、资助能力，以及 选择候选人的共同导师是为了最大限度地发挥他们与项目相关的优势。 James Lokensgard 博士是一位神经炎症专家，他的研究项目和职业发展计划。 小胶质细胞的科学技术和研究与该提案的目的相符。 神经发育和临床前模型专家，用于评估早期生命对大脑的影响。 明尼苏达大学通过学术健康中心和大学对候选人的承诺 儿科确保成功完成拟议的研究。