Intrauterine inflammation is known to be one of the risk factors for periventricular leukomalacia (PVL) that subsequently leads to the development of cerebral palsy. In recent years, microglial cell activation has been implicated in the development of PVL. The long term goal of this study is to understand the cellular and metabolic derangements leading to brain injury during development and use this information to design specific, targeted therapy to prevent the brain injury. The central hypothesis is that endotoxin induced intrauterine inflammation leads to activation of microglial cells in the fetal brain that progresses over time leading to oligodendrocyte damage and white matter injury, and that decreasing the time course of microglial activation will arrest this injury. This hypothesis will be tested in a rabbit model of intrauterine inflammation, by pursuing the following specific aims: (1) Determine the microglial response and white matter injury in the newborn rabbit brain in pups exposed to intrauterine inflammation by assessing changes in uptake of the PET tracer [C-11] PK11195, by microglial numbers and oligodendrocyte loss on histology, by diffusion tensor imaging, and by neurobehavioral changes. (2) Determine whether postnatal anti- inflammatory treatment with minocycline can decrease the time course of microglial cell activation, diminish brain injury and improve neurobehavioral outcome in the neonatal rabbit exposed to intrauterine inflammation as assessed by longitudinal measurements of [C-11] PK11195 uptake, diffusion tensor imaging and neurobehavioral scores in the newborn rabbit brain in pups exposed to endotoxin in utero. We expect that this research will lead to better understanding of the temporal and spatial progression of microglial activation and its relationship to white matter injury in the developing brain using novel non- invasive neuroimaging techniques that can be translated to the clinical setting and can be used to follow the injury and response to therapy. The training objective of this proposal is to achieve investigative independence as a pediatric neurointensivist with expertise in the application of neuroimaging for assessing novel drug therapies in perinatal brain injury. The educational aspect involves supervised research and analyses in the area of neuroimaging with Positron Emission Tomography (PET), in developing the animal model, immunohistochemistry and identification of inflammatory markers and formal, structured training in biostatistics and the ethical conduct of research.
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