IL-1beta regulation of perinatal brain injury

描述（由申请人提供）：在美国，大约12%的活产婴儿早产。子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。使用子宫内炎症的小鼠模型，从局部子宫内脂多糖输注，我们已经证明了兴奋性毒性通路（神经毒性通路作为过量的谷氨酸或类似兴奋性物质的结果）在胎脑中的激活。所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学后遗症的关键机制。沿着胎儿神经元损伤，我们还证实了胎儿脑中IL-1的显著升高。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关键作用。我们实验室的初步工作已经证明，母体给予的IL-1受体拮抗剂，子宫内炎症之前，似乎可以防止，在大脑区域的特定方式，胎儿皮质神经毒性。因此，本研究的目的是研究胎儿大脑中激活的机制，以应对宫内炎症和IL-1的作用，以寻求新的治疗策略，以防止不良的神经系统结果。我们的总体假设是，IL-1介导胎儿大脑皮层损伤， 子宫内炎症，并负责长期的神经系统变化。阐明胎儿IL-1产生导致神经元死亡和长期神经学结果的机制，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。本提案的培训目标是实现作为母胎医学医生-科学家的独立性，其专业知识包括：1）胎儿脑损伤，2）用于识别胎儿/新生儿脑损伤及其对治疗的反应的脑成像，以及3）在子宫内炎症小鼠模型中作为转化工具的神经行为结果评估。该申请人特别适合进行这项研究工作，因为她受过母胎医学医师的培训，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，再加上与一位有成就的、壁外资助的、领先的科学家的指导关系，该科学家的专长是兴奋性毒性和围产期脑损伤。此外，申请人所在机构的环境有利于这项研究的发展，该机构致力于她作为终身教职员工的发展。这项转化研究将对围产期医学领域产生重大影响，因为它不仅将揭示宫内炎症引起胎儿脑损伤的机制，还将为胎儿神经学领域开辟新的途径。 公共卫生相关性：本研究的目的是探讨暴露于宫内炎症导致胎儿脑损伤的机制。本建议的培训目标是实现独立，作为一个产妇-胎儿医学医生，科学家与胎儿脑损伤的专业知识。这项转化研究将对围产期医学领域产生重大影响，因为它不仅将揭示宫内炎症引起胎儿脑损伤的机制，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. PUBLIC HEALTH RELEVANCE: The purpose of this study is to investigate the mechanisms by which exposure to intrauterine inflammation leads to fetal brain injury. The training objective of this proposal is to achieve independence as a Maternal- Fetal Medicine physician-scientist with expertise in fetal brain injury. 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.