Cytokines and the blood-brain barrier in the ovine fetus

羊胎儿的细胞因子和血脑屏障

• 批准号: 9539626
• 负责人: BARBARA S STONESTREET
• 金额: $ 45.2万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-20 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9539626
• 关键词: Address; Aminoisobutyric Acids; Antibodies; Attenuated; Biochemical; Biological Markers; Blocking Antibodies; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Injuries; Cerebral Palsy; Cerebral cortex; Childhood; Data; Development; Developmental Disabilities; Disease; Dose; Exposure to; Fetus; Functional disorder; Gestational Age; Goals; Human; Hypoxia; Hypoxic-Ischemic Brain Injury; Impairment; Individual; Infant; Inflammation; Inflammatory; Infusion procedures; Injury; Interleukin-1 beta; Interleukin-6; Ischemia; Link; Lipopolysaccharides; Measures; Mediating; Mediator of activation protein; Metalloproteases; Methods; Molecular; Monoclonal Antibodies; Neurodevelopmental Disability; Neuroglia; Neurons; Neurophysiology - biologic function; Outcome; Pathogenesis; Pathologic; Pathway interactions; Pericytes; Perinatal Brain Injury; Permeability; Physiological; Play; Poison; Premature Infant; Prevention; Process; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Proteins; Publishing; Radiolabeled; Role; Site; Societies; Stress; Testing; Therapeutic; Therapeutic Intervention; Tight Junctions; base; brain parenchyma; brain tissue; critical period; cytokine; fetal; fetal blood; improved; improved outcome; in utero; injured; innovation; insight; interdisciplinary approach; natural hypothermia; neonatal brain; neonatal hypoxic-ischemic brain injury; neonate; neuroprotection; neurovascular unit; neutralizing monoclonal antibodies; novel; novel strategies; novel therapeutics; premature; prevent; protein expression; protein transport; public health relevance; response; treatment strategy

 DESCRIPTION (provided by applicant): Perinatal brain injury often results in cerebral palsy and neurodevelopmental disability. Consequently, developmental disabilities place a huge burden on society, emphasizing the paramount need for improved prevention/treatment strategies to reduce individual and societal burdens related to perinatal brain damage. Therapeutic strategies are currently not available for infants with brain damage, except for hypothermia, which can only be used in full term infants for hypoxic-ischemic encephalopathy and is only partially protective. Recent studies suggest that fetal inflammation is a strong predictor of perinatal brain injury. Inflammatory processes in utero are likely antecedents of brain damage in preterm infants as cytokine elevations predict neonatal brain damage. The blood-brain barrier (BBB)/neurovascular unit (NVU) is a privileged site consisting of brain micro- vascular endothelia, glia, and neurons that regulate the microenvironment for neural functioning. A novel ap- proach to prevent perinatal brain injury would be to target the BBB with agents to preserve its function to limit entry of toxic substances into brain. This proposal is based on the central hypothesis that cytokines cross the BBB in the fetus to damage the brain and that blockade of cytokines attenuates damage to the BBB/NVU and the brain parenchyma. Our published data show that blocking effects of pro-inflammatory cytokines with systemic infusions of cytokine neutralizing monoclonal antibodies (mAb) attenuate ischemia-related increases in BBB permeability in the ovine fetus. The novel overall goal of this continuation of an R01 is to elucidate the effects of systemic inflammation on BBB/NVU function to determine whether blocking cytokines with systemic antibody infusions attenuates inflammation-related damage to the BBB/NVU/brain parenchyma in the fetus. A multidisciplinary approach to address the specific aims includes physiological, biochemical, pathological, immunohistochemical, and molecular methods. Aim 1 tests the hypothesis that systemic inflammation (induced by LPS) results in increases in BBB permeability measured both with α-aminoisobutyric acid and radiolabeled cytokines, as a function of gestational age, and a result of changes in the NVU. Aim 2 tests the hypothesis that cytokine-specific neutralizing mAbs prevent inflammation-related increases in non- specific BBB permeability, cytokine transport into brain by attenuating damage to the NVU, and, thus, reduce parenchymal brain damage. Aim 3 tests the hypothesis that inflammation-related increases in BBB permeability are prostanoid dependent by determining whether cyclooxygenase inhibition prevents LPS-induced BBB dysfunction. Understanding how the BBB/NVU responds to inflammation and mechanism(s) responsible for damage to BBB/NVU will facilitate development of innovative therapeutic approaches. Treatment of neonates with anti-cytokine mAb would be feasible, as humanized anti-IL-1β antibody is currently in use to treat inflammatory conditions and shows beneficial effects in pediatric trials. This project could provide new insights into novel strategies to prevent brain injury in the human fetus and/or full term and premature infant.

 描述(申请人提供)：围产期脑损伤通常会导致脑瘫和神经发育障碍。因此，发育障碍给社会带来了巨大的负担，强调必须改进预防/治疗战略，以减少与围产期脑损伤有关的个人和社会负担。目前还没有治疗策略可用于脑损伤的婴儿，但低温只能用于足月新生儿的缺氧缺血性脑病，并且只能起到部分保护作用。最近的研究表明，胎儿炎症是围产期脑损伤的强烈预测因素。子宫内的炎症过程可能是早产儿脑损伤的先兆，因为细胞因子的升高预示着新生儿的脑损伤。血脑屏障(BBB)/神经血管单位(NVU)是由脑微血管内皮细胞、神经胶质细胞和神经元组成的特权部位，调节神经功能的微环境。一种预防围产期脑损伤的新方法是用药物靶向血脑屏障，以保持其功能，限制有毒物质进入大脑。这一建议是基于一个中心假设，即细胞因子穿过胎儿的血脑屏障损害大脑，阻断细胞因子可以减轻对血脑屏障/NVU和脑实质的损害。我们发表的数据表明，全身输注细胞因子中和单抗(MAb)可以阻断促炎细胞因子的作用，减轻绵羊胎儿缺血相关的血脑屏障通透性增加。这一R01的新的总体目标是阐明全身炎症对BBB/NVU功能的影响，以确定用全身抗体输注阻断细胞因子是否减轻了对胎儿BBB/NVU/脑实质的炎症相关损害。针对特定目标的多学科方法包括生理、生化、病理学、免疫组织化学和分子方法。目的1验证α-氨基异丁酸和放射性标记细胞因子测定的全身性炎症导致血脑屏障通透性增加的假设，作为胎龄的函数，并作为NVU变化的结果。目的2验证细胞因子特异性中和单抗通过减轻对NVU的损伤而阻止炎症相关的非特异性血脑屏障通透性增加，细胞因子进入脑内，从而减少脑实质损伤的假说。目的通过确定环氧合酶抑制是否能阻止内毒素诱导的血脑屏障功能障碍，来验证炎症相关的血脑屏障通透性增加是前列腺素依赖的假说。了解BBB/NVU如何对炎症作出反应以及BBB/NVU的损害机制(S)将有助于开发创新的治疗方法。用抗细胞因子单抗治疗新生儿是可行的，因为人源化的抗IL-1β抗体目前被用于治疗炎症条件，并在儿科试验中显示出有益的效果。该项目可以为预防人类胎儿和/或足月和早产儿脑损伤的新策略提供新的见解。