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

• 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
• 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

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.

高同型半胱氨酸血症是一种常见的代谢紊乱，会导致血浆总水平显著升高。 血浆同型半胱氨酸。尽管FDA强制在食品中添加叶酸，以试图降低 同型半胱氨酸水平，高同型半胱氨酸血症在老年人群中的发生率仍然相当大。这是 主要原因是随着年龄的增长，营养吸收降低，代谢功能下降。 流行病学研究证实，高同型半胱氨酸血症是神经系统疾病的危险因素。 然而，高同型半胱氨酸血症对神经系统疾病结局的直接影响仍不清楚。 我们的发现现在表明，在高同型半胱氨酸血症条件下的缺血性损伤会导致同时激活 一条新的涉及GluN2A-NMDAR激活的信号通路与规范途径相结合 加重缺血性脑损伤。我们研究的长期目标是开发治疗干预措施 减少高同型半胱氨酸血症对脑缺血及相关神经退行性变的不良影响 精神错乱。这一特定应用的目的是描绘GluN2A-NMDAR介导的 神经炎症在脑缺血损伤的加重中起中心作用 高同型半胱氨酸血症。中心假设是，在高同型半胱氨酸血症的情况下， GluN2A-NMDAR介导的神经元过度释放促炎介质MCP-1和PGE2 结果缺血后小胶质细胞活化增强，外周免疫细胞浸润。这个 拟议的研究将使用(1)原代神经元培养来描绘信号级联，下游 同型半胱氨酸-GluN2A-NMDAR刺激，参与MCP-1和MCP-1的表达和释放 来自神经元的PGE2；(2)高同型半胱氨酸血症大鼠和小鼠，以及一系列条件性基因敲除小鼠 GluN2A-NMDAR在大鼠脑缺血后炎症反应增强中的作用 高同型半胱氨酸血症动物；以及(3)磁共振成像(MRI)和一系列行为测试，以 评价脑缺血后抑制GluN2A-NMDAR信号通路的远期疗效 高同型半胱氨酸血症动物的脑损伤。这项拟议的研究具有重要意义，因为它将填补 知识鸿沟对未来设计新的治疗靶点以减轻中风严重程度至关重要 高同型半胱氨酸血症状态下的结局。