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: 8757399
• 负责人: Ranjana Poddar
• 金额: $ 33.03万
• 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 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8757399
• 关键词: Acceleration; Acute; Adverse effects; Age; Agonist; Alzheimer' s Disease; Amino Acids; Animals; Area; Attenuated; Blood - brain barrier anatomy; Brain Injuries; Cell Culture System; Cell Death; Cells; Cerebral Ischemia; Data; Development; Elderly; Etiology; Evaluation; Folate; Folic Acid; Folic Acid Deficiency; Food; Genetic; Glucose; Glutamates; Goals; Homocysteine; Homocystine; Hyperhomocysteinemia; Incidence; Individual; Injury; Intervention; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Knowledge; Link; MAP Kinase Gene; Magnetic Resonance Imaging; Mediating; Metabolic; Metabolic Diseases; Middle Cerebral Artery Occlusion; Mission; Mitogen-Activated Protein Kinases; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR2A NMDA receptor; National Institute of Neurological Disorders and Stroke; Neurodegenerative Disorders; Neurologic; Neurological outcome; Neuronal Injury; Neurons; Nutritional; Oxidation-Reduction; Oxygen; Parkinson Disease; Pathology; Pathway interactions; Plasma; Play; Population; Public Health; Rattus; Receptor Signaling; Reporter; Research; Risk; Role; Signal Pathway; Signal Transduction; Stroke; Sulfhydryl Compounds; Testing; Therapeutic Agents; Therapeutic Intervention; Vitamin B 12; Vitamin B6; absorption; age related; base; behavior test; brain cell; deprivation; disability; extracellular; fortification; in vivo; inhibitor/antagonist; mitochondrial dysfunction; mortality; nervous system disorder; neuroinflammation; neuron loss; neuroprotection; neurotoxicity; novel; novel strategies; novel therapeutics; public health relevance; research study; stroke therapy; therapeutic target

DESCRIPTION (provided by applicant): Hyperhomocysteinemia is a common metabolic disorder that causes a 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 levels, 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. Emerging evidence suggest that pre-disposition to hyperhomocysteinemic conditions may be associated with aggravation and acceleration of neuronal injury and subsequent brain damage in individuals suffering from Alzheimer's and Parkinson's diseases or acute ischemic stroke. However the pathological implications or the molecular basis of neurological insult in individuals predisposed to hyperhomocysteinemia is yet unknown. Our findings now show that a mild ischemic insult in hyperhomocysteinemic animals exacerbates brain injury. The findings also show that homocysteine-dependent neurotoxicity involves a novel-signaling pathway that is mediated through NR2A- NMDA receptor stimulation. 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 objectives of this particular application are to examine the molecular basis of homocysteine induced neuronal injury and evaluate the long-term progression of ischemic brain damage and neurological deficits in hyperhomocysteinemic animals. The central hypothesis is that homocysteine-NR2A-NMDA receptor signaling triggers a deleterious signaling cascade that acts in concert with ischemia-induced pathways to exacerbate brain injury. The proposed studies will use (1) primary neuronal cultures to delineate the deleterious signaling cascades that are activated following homocysteine-dependent NR2A-NMDA receptor stimulation; and (2) Magnetic resonance imaging (MRI) and a battery of behavioral tests for longitudinal evaluation of ischemic brain injury and neurological outcome in hyperhomocysteinemic animals. The study will further evaluate whether disruption of NR2A-NMDA receptor dependent signaling could minimize brain damage associated with stroke under hyperhomocysteinemic conditions. The proposed research is significant since it will provide the first direct evidence for the role of hyperhomocysteinemia in the progression of ischemic brain injury. Understanding the underlying mechanism(s) of homocysteine induced neuronal injury will facilitate the development of potential targets to attenuate the detrimental effects of hyperhomocysteinemia in cerebral ischemia and other age-related neurodegenerative disorders.

描述（由申请方提供）：高同型半胱氨酸血症是一种常见的代谢紊乱，可导致血浆同型半胱氨酸总水平显著升高。尽管FDA强制要求食品中添加叶酸以降低同型半胱氨酸水平，但老年人群中高同型半胱氨酸血症的发病率仍然相当高。这主要是由于随着年龄的增长，营养吸收减少和代谢功能下降。新出现的证据表明，高同型半胱氨酸血症的易感性可能与患有阿尔茨海默病和帕金森病或急性缺血性中风的个体中神经元损伤和随后的脑损伤的加重和加速有关。然而，高同型半胱氨酸血症易感个体神经损伤的病理学意义或分子基础尚不清楚。我们的研究结果表明，在高同型半胱氨酸血症动物中，轻度缺血性损伤会加重脑损伤。研究结果还表明，同型半胱氨酸依赖性神经毒性涉及通过NR 2A-NMDA受体刺激介导的新信号通路。我们研究的长期目标是开发治疗干预措施，以减少高同型半胱氨酸血症对脑缺血和相关神经退行性疾病的不良影响。该特定应用的目的是检查高半胱氨酸诱导的神经元损伤的分子基础，并评估高同型半胱氨酸血症动物中缺血性脑损伤和神经缺陷的长期进展。中心假设是同型半胱氨酸-NR 2A-NMDA受体信号传导触发有害的信号级联反应，其与缺血诱导的途径协同作用以加重脑损伤。拟定的研究将使用（1）原代神经元培养物来描述在同型半胱氨酸依赖性NR 2A-NMDA受体刺激后激活的有害信号级联;和（2）磁共振成像（MRI）和一系列行为测试，用于纵向评价高同型半胱氨酸血症动物的缺血性脑损伤和神经学结局。该研究将进一步评估NR 2A-NMDA受体依赖性信号传导的破坏是否可以最大限度地减少高同型半胱氨酸血症条件下与卒中相关的脑损伤。这项研究意义重大，因为它将为高同型半胱氨酸血症在缺血性脑损伤进展中的作用提供第一个直接证据。了解同型半胱氨酸诱导的神经元损伤的潜在机制将有助于开发潜在的靶点，以减轻高同型半胱氨酸血症在脑缺血和其他年龄相关的神经退行性疾病中的有害影响。