IL-1beta regulation of perinatal brain injury

描述(申请人提供)：在美国，大约12%的活产是早产的。宫内炎症与这些儿童一系列毁灭性的神经行为障碍有关，包括脑瘫。使用宫内炎症的小鼠模型，通过局部宫内注射脂多糖，我们已经证明了兴奋毒性通路(由于谷氨酸或类似的兴奋物质过量而导致的神经毒性通路)在胎儿大脑中的激活。观察到的胎儿神经元形态和功能的“传播性”破坏可能是导致长期不良神经后遗症的关键机制。在胎儿神经元损伤的同时，我们还发现胎儿大脑中的IL-1显著升高。IL-1在许多涉及兴奋性毒性途径的神经炎性疾病的发病机制中起着关键作用。我们实验室的初步工作表明，在宫内炎症之前，母亲服用IL-1受体拮抗剂似乎可以以大脑区域特异性的方式防止胎儿皮质神经毒性。因此，本研究的目的是探讨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后果。我们的总体假设是IL-1在胎脑皮质损伤中起重要作用。 宫内炎症是导致长期神经系统变化的原因。阐明胎儿IL-1产生导致神经元死亡和长期神经后果的机制，以及这种损伤是否具有性别特异性，将具有重要的治疗意义。这项建议的培训目标是作为一名母胎医学内科医生兼科学家实现独立，在1)胎儿脑损伤，2)脑成像识别胎儿/新生儿脑损伤及其对治疗的反应，以及3)在小鼠宫内炎症模型中作为翻译工具评估神经行为结果。这位申请者特别适合进行这项研究工作，因为她接受过母胎医学医生的培训，她的初步工作涉及在宫内炎症模型中阐明胎儿脑损伤的机制，以及与一位在兴奋毒性和围产期脑损伤方面有专长的有成就的、由外部资助的领先科学家的指导关系。此外，申请人所在机构的环境有利于这项研究的发展，该机构致力于发展她作为终身教职员工的能力。这项转化性研究将对围产期医学领域产生重大影响，因为它不仅将揭示胎儿脑损伤合并宫内炎症的机制，还将为胎儿神经学领域开辟新的途径。

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.