Molecular basis of hyperhomocysteinemia induced brain injury in ischemic stroke

高同型半胱氨酸血症引起缺血性脑卒中脑损伤的分子基础

基本信息

批准号：
10335242
负责人：
Ranjana Poddar
金额：
$ 57.8万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
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：
2014-05-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10335242
关键词：
Acute Adverse effects Age Factors Agonist Amino Acids Animal Model Animals Brain Brain Injuries CCL2 gene Cell Communication Cells Cerebral Ischemia Development Dinoprostone Elderly Folic Acid Food Future Glutamates Goals Homocysteine Hyperhomocysteinemia Immune Incidence Individual Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Intervention Ischemia Ischemic Brain Injury Ischemic Stroke Knockout Mice Knowledge Lead Leukocytes Luciferases MAP Kinase Gene Magnetic Resonance Imaging Mediating Metabolic Metabolic Diseases Micronutrients Middle Cerebral Artery Occlusion Mission Mitogen-Activated Protein Kinases Molecular Mus N-Methyl-D-Aspartate Receptors National Institute of Neurological Disorders and Stroke Neurodegenerative Disorders Neuroimmune Neurologic Neurological outcome Neurons Nuclear Nutritional Pathology Pathway interactions Peripheral Phosphorylation Plasma Play Population Predisposition Prostaglandins Public Health Rattus Reporter Research Risk Factors Role Series Severities Signal Pathway Signal Transduction Stroke Sulfhydryl Compounds Testing Therapeutic Agents Therapeutic Intervention Tumor-infiltrating immune cells Wild Type Mouse Wistar Rats absorption age related neurodegeneration behavior test blood-brain barrier disruption brain cell chemokine conditional knockout cyclooxygenase 2 design disability early onset epidemiology study excitotoxicity experimental study extracellular fortification inducible gene expression inhibitor male mortality nervous system disorder neuroinflammation new therapeutic target novel novel therapeutics response src-Family Kinases stroke outcome transcription factor

项目摘要

Hyperhomocysteinemia is a common metabolic disorder that causes significant increase in the total level of plasma homocysteine. In spite of the FDA-mandated fortification of food with folic acid, as an attempt to lower homocysteine level, the incidence of hyperhomocysteinemia in the elderly population is still quite large. This is mainly due to lowered nutritional absorption and decreased metabolic function with advanced age. Epidemiological studies have established that hyperhomocysteinemia is a risk factor for neurological diseases. However, the direct impact of hyperhomocysteinemia on the outcome of neurological diseases is still not known. Our findings now show that ischemic insult under hyperhomocysteinemic condition leads to concurrent activation of a novel signaling pathway involving GluN2A-NMDAR activation that in conjunction with the canonical pathway exacerbates ischemic brain injury. The long-term goal of our research is to develop therapeutic interventions for reducing the adverse effect of hyperhomocysteinemia on cerebral ischemia and related neurodegenerative disorders. The objective of this particular application is to delineate whether GluN2A-NMDAR mediated neuroinflammation plays a central role in the exacerbation of ischemic brain damage under hyperhomocysteinemic condition. The central hypothesis is that under hyperhomocysteinemic condition, GluN2A-NMDAR-mediated excessive release of the pro-inflammatory mediators MCP-1 and PGE2 from neurons results in augmentation of post-ischemic microglial activation and peripheral immune cell infiltration. The proposed studies will use (1) primary neuronal cultures to delineate the signaling cascade, downstream of homocysteine-GluN2A-NMDAR stimulation, involved in the increased expression and release of MCP-1 and PGE2 from neurons; (2) hyperhomocysteinemic rat and mice, as well as a series of conditional knockout mice to evaluate the role GluN2A-NMDAR in post-ischemic augmentation of inflammatory response in hyperhomocysteinemic animals; and (3) magnetic resonance imaging (MRI) and a battery of behavioral tests to evaluate the long-term efficacy of post-ischemic inhibition of GluN2A-NMDAR signaling pathway in reducing brain damage in hyperhomocysteinemic animals. The proposed research is significant since it will fill a knowledge gap that is critical for future designing of novel therapeutic targets to mitigate the severity of stroke outcome under hyperhomocysteinemic condition.

高脑结晶质血症是一种常见的代谢疾病，可导致总水平显着增加血浆同型半胱氨酸。尽管有叶酸的FDA强化食物的强化，以试图降低同型半胱氨酸水平，老年人群中高型结晶血症的发生率仍然很大。这是主要是由于降低营养吸收和随着年龄的增长而降低了代谢功能。流行病学研究已经确定，高脑结晶质血症是神经系统疾病的危险因素。然而，多栓塞血症对神经系统疾病结果的直接影响尚不清楚。现在，我们的发现表明，在超舒适性状态下缺血性损伤导致同时激活涉及glun2a-nmdar激活的新型信号通路，该通路与规范途径结合加剧缺血性脑损伤。我们研究的长期目标是开发治疗干预措施减少高脑结膜血症对脑缺血和相关神经退行性的不良影响疾病。该特定应用的目的是描述是否介导Glun2a-nmdar 神经炎症在加剧缺血性脑损伤下起着核心作用多层生成状态病。中心假设是，在超脑层状结晶条件下， GLUN2A-NMDAR介导的促炎性介质MCP-1和PGE2的过度释放神经元导致增强缺血后小胶质细胞激活和外周免疫细胞浸润。这拟议的研究将使用（1）主要的神经元培养物来描述信号级联，下游同型半胱氨酸-GLUN2A-NMDAR刺激，参与MCP-1和释放的增加和释放来自神经元的PGE2；（2）多粒性结晶大鼠和小鼠，以及一系列条件敲除小鼠评估Glun2A-NMDAR在炎症后炎症后反应中的作用高脑结晶性动物；（3）磁共振成像（MRI）和一系列行为测试评估减少glun2a-nmdar信号通路的缺血后抑制的长期疗效多脑结晶性动物的脑损伤。拟议的研究很重要，因为它将填充知识差距对于未来设计新型治疗靶标的至关重要，以减轻中风的严重程度在多粒性半胱氨酸血症状态下的结果。