Age-dependent microglial responses in hypoxia-ischemia

描述（由申请人提供）：我的总体职业目标是成为儿科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源于我作为儿科重症监护医生照顾脑损伤儿童的临床经验。在过去的5年里，我在小动物MRI在啮齿动物脑缺血模型中的应用方面发展了专业知识。在培训期间，我将获得额外的尖端神经成像技术和方法的经验，以评估小胶质细胞反应的分子机制在发育中的大脑。一项验证新型PET/MR成像技术的个性化培训将为我提供开发用于研究HI后神经炎症的创新成像技术所需的专业知识。我将在威斯康星大学临床与转化研究所学习统计学、成像方法、免疫学和发育神经生物学方面的正式课程。在加州大学旧金山分校的Vexler实验室和Safar复苏研究中心的Clark实验室实习，将提供评估神经细胞死亡和评估和抑制hi后小胶质细胞激活的新技术培训。为了培养将我的临床前影像学研究转化为临床应用所需的技能，并开始在该领域建立声誉，我将参加儿科神经危重症护理研究小组，这是一个多机构的转化研究网络。我将继续指导脑损伤

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. !