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：
10631173
负责人：
Sujatha Kannan
金额：
$ 57.18万
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/10631173
关键词：
Acids Address Adolescent Age Agonist Area Association Learning Birth 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 Human Image Impaired cognition Impairment In Vitro Infection Inflammation Inflammatory Injury Intravenous Knowledge Learning Learning Disorders Life Link Mediating Memory Metabotropic Glutamate Receptors Microglia Mission Modeling Mus N-acetylaspartate N-acetylaspartylglutamate Neonatal Brain Injury Neurocognitive Neurodevelopmental Disorder Neuroglia Neurons Neuropeptides Neuropharmacology Neuropsychology Newborn Infant Oryctolagus cuniculus Output Pathogenesis Pathology Penetration 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 clinical translation comparative efficacy conditioning cytokine disability disorder prevention efficacy evaluation excitotoxicity eyeblink conditioning fetal glial activation glutamate carboxypeptidase high risk hypoxic ischemic injury improved in utero inhibitor 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.

项目摘要/摘要尽管在新生儿护理和治疗性体温过低，术语和期限方面取得了重大进展新生儿脑病的早产幸存者有发展认知和学习缺陷的高风险即使在没有功能性运动缺陷的情况下。最近的研究已暗示小脑功能障碍与在这些孩子中看到的长期学习障碍。浦肯野细胞开发受损已与小脑联想学习的损害。已显示小胶质细胞在 Purkinje细胞的发展，这是小脑皮层的主要输出神经元。宫内炎症导致小胶质细胞激活导致Purkinje细胞和小脑学习缺陷。小脑中活化的小胶质细胞过表达乙酸酶羧肽酶II（GCPII），，水解丰富的神经肽N-乙酰基谷氨酸盐（NaAg）代谢性谷氨酸受体，mglur3）至N-乙酰天冬氨酸和谷氨酸。降低的NAAG水平具有与认知受损有关。这项研究建议使用使用小胶质细胞GCPII酶使用树突聚合物与纳摩尔有效但脑穿透GCPII抑制剂的偶联偶联（2-- （磷酸甲基）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态在小脑发育中起着至关重要的作用，并抑制上调的GCPII 用D-2PMPA激活的小胶质细胞将导致小脑中的NAAG增加，使Purkinje细胞能够暴露于低剂量内毒素的青少年兔子中的小脑学习和记忆在子宫里。这将通过（1）评估低剂量宫内内毒素暴露对 Purkinje细胞开发，小脑小胶质细胞反应和小脑学习（通过经典的Eykblink测试在母体炎症引起的脑损伤的兔模型中，调理反射）。（2）评估D-的功效 2pmpa介导的小胶质细胞GCPII对Purkinje细胞发育和小脑学习的抑制在6-8周暴露于宫内炎症的兔子的年龄，（3）确定小脑的机制通过NaAg诱导的MGLUR3激活介导的D-2PMPA神经保护。这项研究将提供更好地了解围产期低度的产妇炎症会导致小脑学习长期缺陷。拟议的工作具有创新性，因为它使用了一种新颖而有效的D- 2pmpa结合物以针对小胶质细胞GCPII解决认知和学习缺陷，并使正常小脑在围产期脑损伤的兔模型中的发展。这个多PI的建议将带来围产期/新生儿脑损伤，神经药理学/GCP2和纳米医学的协同专业知识，以及临床翻译以实现这些目标。这项工作可能导致新疗法的发展解决新生儿脑损伤常见的学习缺陷。