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：
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
项目类别：
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&apos 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

项目摘要

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（由申请人提供）：高脑结晶质血症是一种常见的代谢疾病，会导致血浆同型半胱氨酸的总水平显着增加。尽管使用叶酸的FDA加强食物的强化，但作为试图降低同型半胱氨酸水平的尝试，但老年人口中的高脑结合系统血症的发生率仍然很大。这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。新兴的证据表明，对超舒适性半胱氨酸血症状况的分配可能与神经元损伤的加重和加速有关，随后患有阿尔茨海默氏症和帕金森氏病或急性缺血性疾病的人的脑损伤。然而，易于体外结晶血症的个体中神经系统侮辱的病理意义或分子基础尚不清楚。现在，我们的发现表明，超脑类结晶动物的轻度缺血性损伤加剧了脑损伤。研究结果还表明，同型半胱氨酸依赖性神经毒性涉及通过NR2A-NMDA受体刺激介导的新颖信号途径。我们研究的长期目标是开发治疗性干预措施，以减少高脑结构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同型半胱氨酸诱导的神经元损伤的分子基础，并评估多脑结合结论性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-NR2A-NMDA受体信号传导触发了有害的信号传导级联，该级联与缺血诱导的途径一起起作用，以加剧脑损伤。拟议的研究将使用（1）原发性神经元培养物来描述同型半胱氨酸依赖性NR2A-NMDA受体刺激后激活的有害信号级联反应。（2）磁共振成像（MRI）和一系列行为测试，以评估多脑结合会动物的缺血性脑损伤和神经系统结果。该研究将进一步评估NR2A-NMDA受体依赖性信号的破坏是否可以最大程度地减少与心形成性半胱氨酸血症条件下中风相关的脑损伤。拟议的研究很重要，因为它将为高脑结膜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促进潜在靶标的发展，以减轻高脑结膜血症对脑缺血和其他年龄相关的神经退行性疾病的有害作用。