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Inter-alpha-inhibitors in Hypoxic-Ischemic Brain Injury

缺氧缺血性脑损伤中的α间抑制剂

基本信息

批准号：
8715433
负责人：
YOW-PIN LIM
金额：
$ 20.32万
依托单位：
PROTHERA BIOLOGICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2015-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8715433
关键词：
Acute Adult Animals Anti-Inflammatory Agents Anti-inflammatory Attenuated Behavioral Blood Blood flow Brain Brain Hypoxia-Ischemia Brain Injuries Brain Ischemia Cerebral Ischemia Cerebral Ischemia-Hypoxia Cerebral Palsy Cerebrum Cessation of life Cognitive deficits Cytokine Suppression Data Development Epilepsy Experimental Models Fetus Fresh Frozen Plasmas Goals Health Human Hypoxia Immunoglobulins Immunomodulators Incidence Infant Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Intracranial Hemorrhages Ischemia Ischemic-Hypoxic Encephalopathy Kidney Language Development Learning Life Light Longitudinal Studies Measures Memory Mental Retardation Modeling Mus Neonatal Neonatal Brain Injury Neurologic Neurologic Dysfunctions Neurons Newborn Infant Outcome Oxygen Patients Perinatal Brain Injury Phase Plasma Play Premature Birth Premature Infant Premature Labor Prevention strategy Protein Biosynthesis Proteins Public Health Rattus Reperfusion Injury Reperfusion Therapy Risk Role Sepsis Sepsis Syndrome Sheep Shock Short-Term Memory Small Business Innovation Research Grant Testing Therapeutic Therapeutic Effect Therapeutic Intervention Translating Umbilical cord structure base clinically relevant cytokine deprivation inter-alpha-inhibitor natural hypothermia neonatal hypoxic-ischemic brain injury neonate neuron loss novel novel therapeutics premature prevent public health relevance treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Neonatal hypoxia-ischemia (HI) remains a major cause of acute perinatal brain injury, leading ultimately to neurologic dysfunction manifesting as cerebral palsy, mental retardation, and epilepsy. Cerebral oxygen deprivation and/or reduced blood flow due to umbilical cord occlusion, prolonged labor, and/or intracranial hemorrhage produce an inflammatory response contributing to neuronal cell death. Unfortunately, current treatment and prevention strategies in newborns are lacking and inadequate. There are no currently available therapies to prevent/treat and/or attenuate brain damage in premature infants and the only available therapeutic intervention for full term infants is hypothermia, which is only partially protective. Inter-alpha Inhibitor Proteins (IAIP) are naturally derived molecules that have been shown to play an important role in modulating inflammatory response by down-regulating pro-inflammatory cytokines in several experimental models of newborn and adult systemic inflammation and in models of inflammation- induced premature labor. Moreover, decreased IAIP has been shown to accurately predict the development of sepsis in premature infants and decreases in IAIP have been detected following induced ischemia in the ovine fetus brains. Thus, exogenous treatment with IAIP is likely to attenuate inflammation-induced brain injury in neonatal incidences of cerebral ischemia. Our recent data strongly demonstrate the beneficial effects of early administration of IAIP in established models of HI injury in the ovine fetus, neonatal rats and adult mice. Not only does IAIP treatment reduce neuroanatomical injury in the brain of experimental animals, but long-term improvement on learning and memory tasks was achieved. The goal of this Phase I SBIR project is to confirm and obtain proof-of-concept of the neuroprotective effects of IAIP in newborn brain injuries. We hypothesize that IAIP treatment will reduce neuronal death and attenuate the development of ischemic-reperfusion injury in the brain. The Specific Aims of the study are to examine the therapeutic effects and long-term behavioral outcome of delayed IAIP treatment in neonatal rat hypoxic-ischemic brain injury model. The proposed studies have significant translational potential to develop IAIP as a novel agent to prevent/attenuate brain damage in infants at risk for mental retardation.

描述（由申请人提供）：新生儿缺氧缺血（HI）仍然是急性围产期脑损伤的主要原因，最终导致神经功能障碍，表现为脑瘫、智力低下和癫痫。由于脐带阻塞、分娩时间延长和/或颅内出血导致的脑缺氧和/或血流量减少产生炎症反应，导致神经元细胞死亡。不幸的是，目前的新生儿治疗和预防策略是缺乏和不足的。目前没有可用的治疗方法来预防/治疗和/或减轻早产儿的脑损伤，并且对于足月婴儿唯一可用的治疗干预是低温，这仅是一种治疗方法。部分保护。间-α抑制蛋白（IAIP）是天然衍生的分子，其已被证明在新生儿和成人全身性炎症的几种实验模型中以及在炎症诱导的早产模型中通过下调促炎细胞因子而在调节炎症反应中起重要作用。此外，IAIP降低已被证明可以准确预测早产儿败血症的发展，并且在羊胎脑中诱导缺血后检测到IAIP降低。因此，外源性IAIP治疗可能会减轻炎症诱导的脑损伤新生儿脑缺血的发病率。我们最近的数据有力地证明了IAIP早期给药在羊胎儿、新生大鼠和成年小鼠中建立的HI损伤模型中的有益作用。IAIP治疗不仅减少了实验动物大脑的神经解剖损伤，而且实现了学习和记忆任务的长期改善。这个第一阶段SBIR项目的目标是确认和获得IAIP在新生儿脑损伤中的神经保护作用的概念验证。我们假设IAIP治疗将减少神经元死亡并减弱脑缺血再灌注损伤的发展。本研究的具体目的是在新生大鼠缺氧缺血性脑损伤模型中检查延迟IAIP治疗的治疗效果和长期行为结果。拟议的研究具有显着的转化潜力，开发IAIP作为一种新的药物，以预防/减轻婴儿的脑损伤，在精神发育迟滞的风险。