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：孕产妇绒毛膜炎，是妊娠28周的最常见出生原因 被称为“胎儿炎症反应综合征”（FIRS）的胎儿中的严重免疫反应。专业 FIRS的早产儿的后果是长期神经发育残疾的风险要高得多 与没有FIR的早产儿相比。脑损伤可能是由于FIR引起的产前激活而引起的 小胶质细胞，中枢神经系统的常驻免疫细胞。活化的小胶质细胞导致脑损伤 至少有两个重要原因：1）急性产前功能变化会损害脑细胞并转移小胶质细胞 从发展任务和2）发生后产后功能会导致小胶质细胞对产后的异常反应 炎症事件。该提议的核心假设是针对FIRS的治疗策略 - 诱导产前小胶质细胞激活或产后炎症反应的机制将预防或 解决小胶质功能异常并改善神经发育结果。研究的目的 是：1）阐明利用遗传抑制和 定时的离体治疗干预方法和2）测试是否抑制产前小胶质细胞 激活或体内小胶质细胞反应将标准化小胶质功能并预防异常 长期神经发育。将使用FIR和产后研究的鼠模型来评估目标 小胶质功能和长期神经发育结果。预计获得的知识将会 导致对受FIR影响的早产儿的发展发展，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 拟议的发展计划将共同支持追求候选人的长期目标：1） 由新生儿神经免疫学和 神经发育，2）将动物模型发现转化为新生儿临床研究，3） 在国内/国际上的研究结果，以对新生儿实践产生影响，4） 各级学生和学员的教师导师。长期目标将借助 在实验室和教室中的结构化指导和学习将解决直接目标： 提高研究和表现能力，免疫学和神经科学知识，授予技巧以及 学生心理。选择了候选人的副业，以最大程度地发挥其优势 研究项目和职业发展计划。 James Lokensgard博士是一位神经炎症专家 小胶质细胞的科学技术和研究与该提案的目的相匹配。迈克尔·乔治夫博士是 神经发育和临床前模型的专家评估早期生命对大脑的影响。集体， 明尼苏达大学通过学术健康中心和 儿科部确保成功完成拟议的研究。