IL-1beta regulation of perinatal brain injury

描述（由申请人提供）：在美国，大约12%的活产婴儿是早产的。宫内炎症与这些儿童的一系列破坏性神经行为障碍有关，包括脑瘫。利用小鼠宫内炎症模型，通过局部宫内脂多糖输注，我们证明了胎儿大脑中兴奋毒性通路（由于谷氨酸过量或类似兴奋性物质导致的神经毒性通路）的激活。观察到的胎儿神经元形态和功能的“扩散性”破坏可能是导致长期不良神经系统后遗症的关键机制。随着胎儿神经元损伤，我们也证明了IL-1 -¿在胎儿大脑中的显著升高。IL-1在许多涉及兴奋毒性途径的神经炎性疾病的发病机制中起关键作用。我们实验室的初步工作已经证明，母体在宫内炎症之前给予IL-1受体拮抗剂似乎可以以大脑区域特异性的方式预防胎儿皮质神经毒性。因此，本研究的目的是研究胎儿大脑对宫内炎症反应的激活机制和IL-1¿的作用，以寻求新的治疗策略来预防不良的神经系统后果。我们的总体假设是IL-1介导胎儿皮质脑损伤

DESCRIPTION (provided by applicant): In the United States, approximately 12% of all live births are delivered preterm. Intrauterine inflammation has been linked to a devastating spectrum of neurobehavioral disorders in these children, including cerebral palsy. Using a mouse model of intrauterine inflammation, from localized intrauterine lipopolysaccharide infusions, we have demonstrated an activation of excitotoxic pathways (neurotoxic pathways as a result of an excess of glutamate, or similar excitatory substances) in fetal brain. The observed "propagated" disruption of fetal neuronal morphology and function may be a critical mechanism leading to long-term adverse neurological sequelae. Along with the fetal neuronal injury, we have also demonstrated a marked elevation of IL-1¿ in the fetal brain. IL-1¿ plays a key role in the pathogenesis of many neuroinflammatory disorders that involve excitotoxic pathways. Preliminary work from our laboratory has demonstrated that a maternally administered IL-1 receptor antagonist prior to intrauterine inflammation appears to prevent, in a brain-region specific manner, the fetal cortical neurotoxicity. Therefore, the objective of this study is to investigate mechanisms activated in the fetal brain in response to the intrauterine inflammation and the role of IL-1¿, in order to pursue novel therapeutic strategies to prevent adverse neurological outcomes. Our overall hypothesis is that IL-1¿ mediates fetal cortical brain injury in intrauterine inflammation and is responsible for the long-term neurological changes. Elucidating the mechanisms by which fetal IL-1¿ production leads to neuronal death and long-term neurological outcomes, and whether this injury is sex-specific, will have important therapeutic implications. The training objective of this proposal is to achieve independence as a Maternal-Fetal Medicine physician- scientist with expertise in 1) fetal brain injury, 2) brain imaging for identification of fetal/neonatal brain injury and its response to therapeutics, and 3) assessment of neurobehavioral outcomes as translational tools in a mouse model of intrauterine inflammation. This applicant is particularly well suited to perform this research work due to her training as a Maternal-Fetal Medicine physician, her preliminary work involving the elucidation of mechanisms of fetal brain injury in the model of intrauterine inflammation, coupled with a mentoring relationship with an accomplished, extramurally funded, leading scientist whose expertise is in excitotoxicity and perinatal brain injury. Moreover, the environment at the applicant's institution is conducive for the development of this research and the institution is committed to her development as a tenure-track faculty member. This translational research will have a significant IMPACT on the field of perinatal medicine as it will not only uncover mechanisms involved in fetal brain injury with intrauterine inflammation but will also open new avenues in the field of fetal neurology.