Targeting glutamate carboxypeptidase in perinatal brain injury

靶向谷氨酸羧肽酶在围产期脑损伤中的作用

基本信息

批准号：
10530903
负责人：
Sujatha Kannan
金额：
$ 53.78万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10530903
关键词：
Acids Address Adolescent Age Agonist Area Blinking Brain Brain Injuries Cell Count Cells Cerebellar Cortex Cerebellar Diseases Cerebellum Cerebral Palsy Child Cognition Cognitive Data Dendrimers Development Dose Electrophysiology (science)Endotoxins Ensure Enzymes Etiology Exhibits Experimental Autoimmune Encephalomyelitis Exposure to FOLH1 gene Functional disorder Glutamates Health Health Care Costs Histology Image Impaired cognition Impairment In Vitro Infection Inflammation Inflammatory Injury Intravenous Knowledge Lead Learning Learning Disorders Life Link Mediating Memory Metabotropic Glutamate Receptors Microglia Mission Modeling Motor Mus N-acetylaspartate N-acetylaspartylglutamate Neonatal Brain Injury Neurocognitive Neurodevelopmental Disorder Neuroglia Neurons Neuropeptides Neuropharmacology Neuropsychology Newborn Infant Oryctolagus cuniculus Output Pathogenesis Pathology Pentanes Perinatal Perinatal Brain Injury Phagocytosis Play Premature Infant Public Health Purkinje Cells Reflex action Regulation Research Role Saline School-Age Population Slice Survivors Testing Therapeutic Thick Time Translational Research Translations United States National Institutes of Health Up-Regulation Work antagonist base classical conditioning clinical translation comparative efficacy conditioning cytokine disability disorder prevention efficacy evaluation eyeblink conditioning fetal glial activation glutamate carboxypeptidase high risk hypoxic ischemic injury improved in utero inhibitor injury prevention innovation intrauterine inflammation metabotropic glutamate receptor 3 motor deficit motor disorder mouse model nanomedicine nanomolar natural hypothermia neonatal care neonatal encephalopathy neuroinflammation neuroprotection novel novel therapeutics overexpression perinatal period postnatal preadolescence prenatal exposure receptor response spasticity targeted treatment

项目摘要

Project summary/abstract Despite significant advances in neonatal care and implementation of therapeutic hypothermia, term and preterm survivors of neonatal encephalopathy are at high risk for developing cognitive and learning deficits even in the absence of functional motor deficits. Recent studies have implicated cerebellar dysfunction with the long-term learning disorders seen in these children. Impaired Purkinje cell development has been linked to impairment in cerebellar associative learning. Microglia have been shown to play a major role in the development of Purkinje cells, the primary output neurons of the cerebellar cortex. Intrauterine inflammation leads to microglial activation that results in maldevelopment of the Purkinje cells and cerebellar learning deficits. Activated microglia in the cerebellum overexpress the enzyme glutamate carboxypeptidase II (GCPII), which hydrolyzes the abundant neuropeptide N-acetylaspartylglutamate (NAAG, a specific agonist of the metabotropic glutamate receptor, mGluR3) to N-acetyl-aspartate and glutamate. Reduced NAAG levels have been linked to impaired cognition. This study proposes to specifically target microglial GCPII enzyme using dendrimer conjugated to the nanomolar potent but poorly brain penetrating GCPII inhibitor 2PMPA (2- (phosphonomethyl) pentane-1,5-dioic acid) (D-2PMPA). The central hypothesis is that normal microglial function and dynamics play a critical role in cerebellar development, and inhibiting upregulated GCPII in activated microglia with D-2PMPA will lead to increased NAAG in the cerebellum enabling normal Purkinje cell development and improving cerebellar learning and memory in juvenile rabbits exposed to low dose endotoxin in utero. This will be tested by (1) Evaluating the effects of low dose intrauterine endotoxin exposure on Purkinje cell development, cerebellar microglial response and cerebellar learning (tested by classical eyeblink conditioning reflex) in a rabbit model of maternal inflammation induced brain injury. (2) Evaluate efficacy of D- 2PMPA mediated microglial GCPII inhibition on Purkinje cell development and cerebellar learning at 6-8 weeks of age in rabbits exposed to intrauterine inflammation and (3) Determine mechanisms of cerebellar neuroprotection by D-2PMPA mediated by NAAG induced activation of mGluR3. This study will provide a better understanding of how low-grade maternal-fetal inflammation in the perinatal period can lead to cerebellar learning deficits long term. The proposed work is innovative because it uses a novel and potent D- 2PMPA conjugate to target microglial GCPII for addressing cognitive and learning deficits and enable normal development of the cerebellum in a rabbit model of perinatal brain injury. This Multi-PI proposal will bring synergistic expertise in perinatal/neonatal brain injury, neuropharmacology/GCP2 and nanomedicine, and clinical translation to accomplish these aims. This work can lead to the development of novel therapies to address learning deficits commonly seen with neonatal brain injury.

项目概要/摘要尽管新生儿护理和低温治疗的实施取得了重大进展，足月和新生儿脑病的早产幸存者出现认知和学习缺陷的风险很高即使没有功能性运动缺陷。最近的研究表明小脑功能障碍与这些儿童出现长期学习障碍。浦肯野细胞发育受损与小脑联想学习障碍。小胶质细胞已被证明在浦肯野细胞（小脑皮质的主要输出神经元）的发育。宫内炎症导致小胶质细胞激活，导致浦肯野细胞和小脑学习发育不良赤字。小脑中激活的小胶质细胞过度表达谷氨酸羧肽酶 II (GCPII)，它水解丰富的神经肽 N-乙酰天冬氨酰谷氨酸（NAAG，一种特定的激动剂）代谢型谷氨酸受体 (mGluR3) 转化为 N-乙酰基天冬氨酸和谷氨酸。 NAAG 水平降低与认知受损有关。本研究提出利用小胶质细胞 GCPII 酶进行特异性靶向与纳摩尔强效但脑穿透性差的 GCPII 抑制剂 2PMPA (2- (膦酰基甲基)戊烷-1,5-二酸)(D-2PMPA)。中心假设是正常的小胶质细胞功能和动力学在小脑发育中起着至关重要的作用，并抑制 GCPII 的上调用 D-2PMPA 激活小胶质细胞将导致小脑中的 NAAG 增加，从而使浦肯野细胞保持正常状态低剂量内毒素暴露幼兔的发育和小脑学习记忆的改善在子宫内。这将通过 (1) 评估低剂量宫内内毒素暴露对浦肯野细胞发育、小脑小胶质细胞反应和小脑学习（通过经典眨眼测试条件反射）在母体炎症引起的脑损伤的兔子模型中。 (2) 评价D-的功效 2PMPA 介导的小胶质细胞 GCPII 对浦肯野细胞发育和 6-8 周小脑学习的抑制暴露于宫内炎症的兔子的年龄和（3）确定小脑的机制 NAAG 介导的 D-2PMPA 的神经保护作用诱导 mGluR3 的激活。这项研究将提供更好地了解围产期低度母婴炎症如何导致小脑的长期学习缺陷。拟议的工作具有创新性，因为它使用了一种新颖且有效的 D- 2PMPA 结合靶向小胶质细胞 GCPII，以解决认知和学习缺陷并促进正常围产期脑损伤兔模型中小脑的发育。这项多 PI 提案将带来围产期/新生儿脑损伤、神经药理学/GCP2 和纳米医学方面的协同专业知识，以及临床翻译来实现这些目标。这项工作可能会导致新疗法的开发解决新生儿脑损伤常见的学习缺陷。