Age-dependent microglial responses in hypoxia-ischemia

缺氧缺血时年龄依赖性小胶质细胞反应

• 批准号: 8697152
• 负责人: Peter A Ferrazzano
• 金额: $ 19.2万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697152
• 关键词: ARHGEF5 gene; Adolescent; Adult; Affect; Age; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Brain region; Caring; Cerebral Ischemia; Child; Child Care; Childhood; Clinic; Clinical; Clinical Research; Clinical Trials; Core Facility; Corpus striatum structure; Critical Care; Cytokine Activation; Data; Development; Developmental Disabilities; Ensure; Environment; Exhibits; Flow Cytometry; Funding; Future; Goals; Hippocampus (Brain); Housing; Image; Imaging Techniques; Immunologic Monitoring; Immunology; Impairment; Infant; Inflammatory; Inflammatory Response; Injury; Institutes; Institution; Interleukin-10; International; Ipsilateral; Ischemia; Knock-out; Learning; Light; Location; Magnetic Resonance Imaging; Measures; Mediating; Mentors; Methods; Microglia; Microscopy; Minocycline; Modeling; Molecular; Mus; Nervous System Physiology; Neurologic; Neuronal Injury; Outcome; Outcome Measure; Pediatric Brain Injury; Phagocytosis; Physicians; Plant Roots; Positron-Emission Tomography; Postdoctoral Fellow; Process; Production; Research; Research Methodology; Research Personnel; Research Proposals; Rest; Resuscitation; Rodent Model; Scientist; Stroke; Survivors; Techniques; Testing; Therapeutic; Time; Training; Translating; Translational Research; Travel; United States; Universities; Validation; Wages; Wisconsin; age related; aging brain; animal resource; behavior test; career; career development; cytokine; developmental neurobiology; experience; follow-up; gray matter; imaging modality; improved; innovation; interest; myelinopathy; neurodevelopment; neuroimaging; neuroinflammation; neuron loss; neuronal survival; novel; pediatric department; postnatal; pre-clinical; public health relevance; ranpirnase; regional difference; response; skills; statistics; synaptogenesis; therapy development; treatment strategy; white matter

DESCRIPTION (provided by applicant): My overall career goal is to become a leader in the field of pediatric brain injury research. My interest in the effect of neurodevelopment on responses to cerebral ischemia is rooted in my clinical experience caring for children with brain injury as a Pediatric Critical Care Physician. Over the past 5 years, I have developed an expertise in the use of small animal MRI in rodent models of cerebral ischemia. During the training period, I will gain additional experience in cutting edge neuroimaging techniques and methods for assessing molecular mechanisms of microglial responses in the developing brain. An individualized training in validation of a novel PET/MR imaging technique will provide me with the expertise I need to develop innovative imaging techniques for studying neuroinflammation after HI. I will take formal coursework through the University of Wisconsin's Institute for Clinical and Translational Research in statistics, imaging methods, immunology, and developmental neurobiology. Externships to the Vexler Lab at UCSF and the Clark Lab at the Safar Center for Resuscitation Research will provide training in new techniques for assessing neuronal cell death and for assessing and inhibiting microglial activation post-HI. To develop the skills necessary to translate my pre-clinical imaging studies into clinical use, and to begin to establish a reputation in the field, I will participate in the Pediatric Neurocritical Care Researc Group, a multi-institution translational research network. I will continue to direct a brain injury follow-up clinic, which will improve my understanding of outcomes from pediatric brain injury, and create a framework for measuring outcomes in future clinical trials. All of these steps will facilitate my successful transition to independence. Environment: The University of Wisconsin is one of the premier research institutions in the United States with over 170 neuroscientists on campus. The Department of Pediatrics has provided start-up funds, lab space, and salary support for a research associate, and 9 months of protected research time per year. The location of my lab at the Waisman Center for Developmental Disabilities research is the ideal environment for conducting translational research in developmental brain injuries. The Waisman Center houses the labs of my Mentors and other experts in developmental brain injuries and neuroimaging, and provides core facility resources for animal imaging, behavioral testing, microscopy, and flow cytometry. We have assembled a team of experienced mentors with expertise in the fields vital to my research: molecular mechanisms of ischemia, myelinopathies, and neuroinflammation, and pre-clinical and clinical neuro-imaging. This optimal research environment will ensure that my transition into an independent physician scientist is successful. Research: Cerebral ischemia affects over 20,000 infants and children every year in the US, and treatment options are limited. Therapies that mitigate the neuroinflammatory response to ischemia have been recognized as a promising neuroprotective strategy. However, the microglia-mediated inflammatory response to ischemia in the developing brain is not well understood. In the immature brain, microglial cells are activated for phagocytosis of cellular debris during synaptogenesis, and it is unknown how this predominance of activated microglia impacts ischemic injury. In our preliminary studies we found both regional and developmental differences in microglial responses to hypoxia-ischemia (HI): early microglia activation in the hippocampus compared to other brain regions, and increased microglial responses in postnatal day 9 (P9) mice compared to P30 mice. We hypothesize that the ongoing differentiation and activation of microglia in the immature brain predisposes it to a more vigorous pro-inflammatory response to HI than juvenile and adult brains, and that age- and region- dependent differences in microglial responses result in different profiles of neuronal injury. These hypotheses will be tested in the following aims: Specific Aim 1: Test our hypothesis that increased microglial activation prior to injury in immature brains contributes to a more vigorous microglial response to HI. Specific Aim 2: Test our hypothesis that region- and age-dependent differences in microglial responses result in different profiles of neuronal injury using a microglial inhibition approach. I summary, this research proposal will investigate the novel hypothesis that the microglia response to ischemia is developmentally regulated. The completion of this study will shed new light on microglia function after hypoxia- ischemia in the developing brain, and determine the potential benefit of microglial inhibition after HI. Completion of the Training Plan in advanced neuroimaging, neuroinflammation, and translational research will provide me with a unique skill set that will allow me to capitalize on my clinical expertise in neurocritical care and develop new treatment strategies targeting the neuroinflammatory response to pediatric cerebral ischemia. !

描述（由申请人提供）：我的整体职业目标是成为小儿脑损伤研究领域的领导者。我对神经发育对脑缺血反应的影响的兴趣植根于我照顾脑损伤儿童作为儿科重症监护医师的临床经验。在过去的5年中，我在脑缺血模型中使用了小动物MRI的专业知识。在培训期间，我将获得额外的经验，以评估发育中大脑中小胶质细胞反应的分子机制的尖端神经成像技术和方法。对新型宠物/MR成像技术进行验证的个性化培训将为我提供我需要开发创新成像技术来研究神经炎症后的专业知识。我将通过威斯康星大学的统计，成像方法，免疫学和发育神经生物学的临床和转化研究研究所进行正式课程。在UCSF的Vexler Lab和Safar复苏研究中心的Clark Lab的实习将提供用于评估神经元细胞死亡以及评估和抑制小胶质细胞激活的新技术的培训。为了开发将我的临床成像研究转化为临床使用所需的技能，并开始在该领域建立声誉，我将参加多机构翻译研究网络的小儿神经易政治护理研究小组。我将继续引导脑损伤 随访诊所，这将提高我对小儿脑损伤结果的理解，并创建一个框架，以测量未来的临床试验中的结果。所有这些步骤将有助于我成功过渡到独立。环境：威斯康星大学是美国的主要研究机构之一，校园内有170多名神经科学家。儿科部为研究助理提供了启动资金，实验室空间和薪水支持，每年提供9个月的受保护时间。我的实验室在Waisman发育残疾研究中心的位置是进行发育性脑损伤转化研究的理想环境。 Waisman Center拥有我的导师和其他专家在发育性脑损伤和神经影像方面的实验室，并为动物成像，行为测试，显微镜和流式细胞仪提供核心设施资源。我们已经组建了一支经验丰富的导师团队，该团队在我的研究中至关重要的领域：缺血，骨髓病和神经炎症的分子机制，以及临床前和临床神经图像。这种最佳研究环境将确保我向独立医师科学家的过渡成功。研究：脑缺血在美国每年都会影响20,000多名婴儿和儿童，治疗选择受到限制。减轻对缺血的神经炎症反应的疗法已被认为是一种有希望的神经保护策略。但是，尚不清楚小胶质细胞介导的对发育中的脑缺血的炎症反应。在未成熟的大脑中，小胶质细胞在突触发生过程中被激活以吞噬细胞碎屑，而活化的小胶质细胞的这种优势如何影响缺血性损伤，这是未知的。在我们的初步研究中，我们发现与其他大脑区域相比，海马中的小胶质细胞反应（HI）小胶质细胞反应（HI）：早期的小胶质细胞激活，与P30小鼠相比，在产后第9（P9）小鼠中的小胶质细胞反应增加。我们假设未成熟大脑中的小胶质细胞的持续分化和激活使它对HI的促炎反应比少年和成年大脑更具剧烈的促炎反应，并且小胶质细胞反应的年龄和区域依赖性差异会导致神经元损伤的不同特征。这些假设将在以下目的中进行检验：具体目的1：测试我们的假设，即在不成熟大脑中受伤之前增加的小胶质细胞激活有助于更剧烈的小胶质细胞反应 你好。具体目的2：测试我们的假设，即小胶质细胞反应中区域和年龄依赖性差异会导致使用小胶质抑制方法的神经元损伤的不同特征。总而言之，该研究建议将调查小胶质细胞对缺血的反应受发展调节的新假设。这项研究的完成将为发育中的大脑缺氧 - 缺血后的小胶质细胞功能提供新的启示，并确定HI后小胶质细胞抑制的潜在益处。完成高级神经影像学，神经炎症和翻译研究的培训计划将为我提供独特的技能，这将使我能够利用我的神经行为护理的临床专业知识并发展新的技能 针对小儿脑缺血的神经炎症反应的治疗策略。呢