Cytokines and the blood-brain barrier in the ovine fetus
羊胎儿的细胞因子和血脑屏障
基本信息
- 批准号:9108608
- 负责人:
- 金额:$ 47.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAminoisobutyric AcidsAntibodiesAttenuatedBiochemicalBiological MarkersBlocking AntibodiesBlood - brain barrier anatomyBlood VesselsBrainBrain InjuriesCerebral PalsyCerebral cortexChildhoodDataDevelopmentDevelopmental DisabilitiesDiseaseDoseExposure toFetusFunctional disorderGestational AgeGoalsHumanHypoxiaHypoxic-Ischemic Brain InjuryIndividualInfantInflammationInflammatoryInfusion proceduresInjuryInterleukin-1 betaInterleukin-6IschemiaLinkLipopolysaccharidesMeasuresMediatingMediator of activation proteinMetalloproteasesMethodsMolecularMonoclonal AntibodiesNeurodevelopmental DisabilityNeurogliaNeuronsNeurophysiology - biologic functionOutcomePathogenesisPathway interactionsPericytesPerinatalPerinatal Brain InjuryPermeabilityPhysiologicalPlayPoisonPremature InfantPreventionProcessProstaglandin-Endoperoxide SynthaseProstaglandinsProteinsPublishingRadiolabeledRoleSiteSocietiesStressTestingTherapeuticTherapeutic InterventionTight JunctionsVascular Endotheliumbasebrain parenchymabrain tissuecritical periodcytokinefetalfetal bloodimprovedimproved outcomein uteroinjuredinnovationinsightinterdisciplinary approachnatural hypothermianeonatal brainneonatal hypoxic-ischemic brain injuryneonateneuroprotectionneurovascular unitneutralizing monoclonal antibodiesnovelnovel strategiesnovel therapeuticsprematurepreventprotein expressionprotein transportpublic health relevanceradiotracerresponsetreatment strategy
项目摘要
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(由申请人提供):围产期脑损伤往往导致脑瘫和神经发育障碍。因此,发育性残疾给社会带来了巨大负担,突出表明迫切需要改进预防/治疗战略,以减少与围产期脑损伤有关的个人和社会负担。治疗策略目前不适用于脑损伤的婴儿,除了低温,它只能用于足月婴儿的缺氧缺血性脑病,只有部分保护。最近的研究表明,胎儿炎症是围产期脑损伤的一个强有力的预测因素。子宫内的炎症过程可能是早产儿脑损伤的先兆,因为细胞因子升高可预测新生儿脑损伤。血脑屏障(BBB)/神经血管单元(NVU)是由脑微血管内皮细胞、神经胶质细胞和调节神经功能微环境的神经元组成的特权部位。预防围产期脑损伤的一种新方法是用药物靶向血脑屏障,以保护其功能,限制有毒物质进入大脑。该提议基于中心假设,即细胞因子穿过胎儿中的BBB以损伤脑,并且细胞因子的阻断减弱对BBB/NVU和脑实质的损伤。我们发表的数据表明,阻断促炎性细胞因子与细胞因子中和单克隆抗体(mAb)的全身输注的作用减弱缺血相关的增加,在羊胎儿的血脑屏障通透性。R 01延续的新总体目标是阐明全身性炎症对BBB/NVU功能的影响,以确定全身性抗体输注阻断细胞因子是否减轻胎儿中BBB/NVU/脑实质的炎症相关损伤。一个多学科的方法来解决的具体目标,包括生理学,生物化学,病理学,免疫组织化学和分子方法。目的1检验以下假设:全身性炎症(由LPS诱导)导致BBB渗透性增加(用α-氨基异丁酸和放射性标记的细胞因子测量),作为胎龄的函数,以及NVU变化的结果。目的2测试以下假设:精氨酸特异性中和mAb通过减弱对NVU的损伤来防止非特异性BBB渗透性、细胞因子转运到脑中的炎症相关增加,并因此减少实质脑损伤。目的3通过确定环氧合酶抑制剂是否阻止LPS诱导的BBB功能障碍来检验炎症相关的BBB通透性增加是前列腺素依赖性的假设。了解BBB/NVU如何对炎症做出反应以及导致BBB/NVU损伤的机制将促进创新治疗方法的开发。用抗细胞因子mAb治疗新生儿是可行的,因为人源化抗IL-1β抗体目前用于治疗炎症性疾病,并在儿科试验中显示出有益效果。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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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BARBARA S STONESTREET其他文献
BARBARA S STONESTREET的其他文献
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{{ truncateString('BARBARA S STONESTREET', 18)}}的其他基金
Neuroprotective Strategy: Novel Purine Derivatives for Neonatal Hypoxia-ischemia
神经保护策略:治疗新生儿缺氧缺血的新型嘌呤衍生物
- 批准号:
10219376 - 财政年份:2021
- 资助金额:
$ 47.32万 - 项目类别:
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:
8089977 - 财政年份:2010
- 资助金额:
$ 47.32万 - 项目类别:
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:
7863942 - 财政年份:2009
- 资助金额:
$ 47.32万 - 项目类别:
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:
7351437 - 财政年份:2008
- 资助金额:
$ 47.32万 - 项目类别:
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:
8242876 - 财政年份:2008
- 资助金额:
$ 47.32万 - 项目类别:
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:
7843699 - 财政年份:2008
- 资助金额:
$ 47.32万 - 项目类别:
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 - 财政年份:2008
- 资助金额:
$ 47.32万 - 项目类别:
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:
8066458 - 财政年份:2008
- 资助金额:
$ 47.32万 - 项目类别:
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:
7615739 - 财政年份:2008
- 资助金额:
$ 47.32万 - 项目类别:
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:
9977229 - 财政年份:2008
- 资助金额:
$ 47.32万 - 项目类别: