The Role of Complement in Cerebrospinal Fluid Shunt Infections

补体在脑脊液分流感染中的作用

• 批准号: 10395980
• 负责人: Gwenn L Skar
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10395980
• 关键词: Address; Adjuvant; Age; Alzheimer' s Disease; Animal Model; Antibiotic Therapy; Astrocytes; Award; Bacteria; Bacterial Meningitis; Brain; Catheters; Cerebral Edema; Cerebrospinal fluid shunts procedure; Child; Childhood; Chronic; Clinical; Clinical Medicine; Communicable Diseases; Complement; Complement 1q; Complement Activation; Complement Inactivators; Complication; Data; Development; Development Plans; Disease; Effector Cell; Etiology; Foundations; Future; Goals; Hemorrhage; Homeostasis; Human; Hydrocephalus; Immune; Infection; Inflammatory; Intracranial Hypertension; Intrathecal Space; Kinetics; Knock-out; Knockout Mice; Knowledge; Lead; Lectin; LoxP-flanked allele; Mediating; Microglia; Molecular; Multiple Sclerosis; Mus; Nerve Degeneration; Nervous System Trauma; Neuraxis; Neurologic; Neurologic Deficit; Neurosurgeon; Outcome; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Performance; Physicians; Procedures; Risk; Risk Factors; Role; Schools; Scientist; Seizures; Shunt Device; Source; Specialist; Staphylococcus epidermidis; Stroke; System; Technical Expertise; Testing; Time; Training; Traumatic Brain Injury; United States; adverse outcome; animal tissue; base; brain tissue; career development; complement C3 precursor; complement pathway; conditional knockout; experience; experimental study; high risk; improved; knockout animal; knowledge base; macrophage; mortality; mouse model; nervous system disorder; neuron loss; new therapeutic target; novel strategies; novel therapeutics; pathogen; pediatric patients; premature; response; retinogeniculate; synaptic pruning; therapeutic target

PROJECT SUMMARY Cerebrospinal fluid shunt infections are a frequent and serious complication of the treatment of hydrocephalus, occurring in 5-30% of patients1, 2. These infections are associated with significant long-term neurologic sequelae such as lower IQ, poor school performance and increased risk of seizures 9-13. The mechanisms responsible for the severe neurologic damage associated with shunt infection are unknown. Studies have demonstrated the role of complement in normal neurologic development through developmentally appropriate complement mediated synaptic pruning by microglia 19,20,22. Additional studies have revealed the role of complement in a variety of neurologic disorders and infection supporting a central role for complement in central nervous system homeostasis and pathology24-33. My preliminary studies in an animal model of shunt infection have demonstrated elevated levels of the complement components C3 and C5 in brain tissue at day 5 and 10 when bacterial burdens are low, suggesting complement may mediate the neurologic damage associated with shunt infections. This is further supported by my preliminary data demonstrating that synaptic pruning is less dramatic in C3 knockout mice. The overall objective of this proposal is to understand the role of complement in a murine model of CNS catheter infection, to facilitate the future identification of novel therapeutic targets to limit neurologic damage in pediatric patients. Understanding the mechanisms whereby complement mediates neurologic damage would allow us to take advantage of many complement inhibitors that are being developed for clinical medicine as potential adjuvants to antibiotic therapy to improve long-term patient outcomes 35,36. Our central hypothesis is that complement components induce microglial-mediated synaptic pruning and are responsible for late-stage cerebral edema. To test this hypothesis, we will perform experiments outlined in two specific aims. In Aim 1, we will identify the primary mode of complement pathway activation during CNS S. epidermidis catheter-associated infection and functional importance. In Aim 2, we will define the molecular mechanisms of complement-mediated damage during CNS catheter infection. Finally, the candidate is a pediatric infectious disease specialist with a long-standing experience investigating shunt infections. She is a well-supported candidate with the goal of becoming a physician scientist and would highly benefit from a Clinical Scientist Development Award.

项目摘要 脑脊液分流感染是脑积水治疗中常见的严重并发症， 发生在5-30%的患者1，2.这些感染与严重的长期神经系统损害有关。 后遗症，如智商较低，学习成绩差，癫痫发作的风险增加9-13。的机制 与分流感染相关的严重神经损伤的原因尚不清楚。 研究已经证明了补体在正常神经发育中的作用， 适当的补体通过小胶质细胞介导的突触修剪19，20，22。更多的研究表明， 补体在各种神经系统疾病和感染中的作用支持补体的中心作用 在中枢神经系统稳态和病理学中的作用24 -33。分流术动物模型的初步研究 感染后第5天脑组织中补体成分C3和C5水平升高 细菌负荷低时为10，提示补体可能介导神经系统损伤 与分流管感染有关我的初步数据进一步证实了这一点， 修剪在C3敲除小鼠中不太显著。本建议的总体目标是了解 补体在CNS导管感染的小鼠模型中的表达，以便于将来鉴定新的 治疗靶点，以限制儿科患者的神经损伤。了解机制 补体介导神经损伤的机制， 正在开发用于临床医学的补体抑制剂作为潜在的佐剂， 抗生素治疗以改善患者的长期预后35，36. 我们的中心假设是补体成分诱导小胶质细胞介导的突触修剪， 导致晚期脑水肿为了验证这一假设，我们将进行两个实验， 具体目标。在目的1中，我们将确定CNS S期间补体途径激活的主要模式。 表皮导管相关感染和功能的重要性。在目标2中，我们将定义分子 CNS导管感染期间补体介导的损伤机制。 最后，候选人是儿科传染病专家，具有长期的调查经验， 分流管感染她是一个得到很好支持的候选人，目标是成为一名医生科学家， 获得临床科学家发展奖。