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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.

高同型半胱氨酸血症是一种常见的代谢性疾病，可导致血清总水平显著升高