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. !

Public Health Relevance

This project will investigate age- and region- dependent differences in the microglia-mediated neuroinflammatory response to cerebral ischemia. The completion of this study will shed new light on microglia function after hypoxia-ischemia in the developing brain, and determine the potential therapeutic benefit of microglial inhibition after cerebral ischemia.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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NST-2 Subcommittee (NST)
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Koenig, James I
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University of Wisconsin Madison
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