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PROTEIN CARBONYLATION AND AXONAL DAMAGE IN EAE

EAE 中的蛋白质羧化和轴突损伤

基本信息

批准号：
8242025
负责人：
OSCAR A BIZZOZERO
金额：
$ 26.46万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242025
关键词：
Active Immunization Acute Affect Aldehydes Amines Amino Acids Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Axon Biochemical Brain Cell Death Central Nervous System Diseases Cessation of life Chemical Structure Chemicals Chronic Clinical Management Cytoskeletal Proteins Data Demyelinating Diseases Demyelinations Development Disease Experimental Autoimmune Encephalomyelitis Experimental Designs Female Functional disorder Future Goals Health Histidine Human Hydralazine Hydrazines Impairment Inflammation Inflammatory Injury Ketones Laboratories Lead Lesion Measures Metabolic Metabolic Pathway Metabolism Microglia Mitochondria Modification Molecular Multiple Sclerosis Mus Nature Nervous System Trauma Neurons Outcome Oxidants Oxidation-Reduction Oxidative Stress Patients Pattern Penicillamine Peptides Pharmaceutical Preparations Play Post-Translational Protein Processing Process Protein Inhibition Proteins Proteomics Rattus Reactive Oxygen Species Relapse Reporting Role SJL Mouse Series Source Spinal Cord Staging Stress System Techniques Testing Therapeutic Tissues Work base carbonyl group central nervous system demyelinating disorder design disability effective therapy improved in vivo inhibitor/antagonist macrophage mouse model nervous system disorder neuronal cell body novel prevent protein function research study therapeutic development young adult

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to define and characterize the mechanisms underlying tissue injury in multiple sclerosis, the most common demyelinating disease of the central nervous system in humans. In recent years, oxidative stress has been implicated in the pathophysiology of both multiple sclerosis and its animal model, experimental allergic encephalomyelitis (EAE). Reactive oxygen species (ROS) are released by activated macrophages/microglia or are endogenously generated by dysfunctional mitochondria in the nerve cells. Although there is unquestionable experimental evidence demonstrating that oxidative stress plays a causal role in these disorders, the precise mechanism(s) by which ROS produces tissue damage is far from clear. A major consequence of ROS accumulation is the non-enzymatic introduction of aldehydes or ketones into specific amino acid residues of proteins (i.e. carbonylation). Based on recent reports regarding the molecular and cellular consequences of protein carbonylation in other systems and a number of important findings from our laboratory, we hypothesize that a major outcome of oxidative stress in EAE is the carbonylation of neuronal proteins, which contributes to tissue damage and axonal injury. We also put forth the idea that inhibition of protein carbonylation will be therapeutic in this disease. To test our hypothesis, we will measure the levels of protein carbonyls in the spinal cord and brain of remitting/relapsing EAE mice in relationship to well-established pathological hallmarks of the disease (inflammation, neuronal death, axonal damage and demyelination). These studies will employ state-of the-art biochemical and immunocytochemical techniques. We will then identify the oxidized proteins in the inflammatory and degenerative stages of the disease by redox proteomics, and will ascertain both the chemical nature and origin of the oxidizing species from the type of carbonylated amino acid residues produced. Finally, we will examine the ability of various carbonyl scavengers and metabolic inhibitors to prevent tissue injury and axonal damage in EAE animals. If successful, these studies will uncover a novel molecular mechanism by which oxidative stress causes chronic disability in demyelinating disorders. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS) is a neurological disorder that affects approximately 1 in 700 young adults in the US. We have recently observed that a special type of oxidative process called carbonylation modifies several brain proteins from MS patients. These modifications affect protein function and likely contribute to tissue injury in this devastating disease. Using a mouse model of MS, we will determine whether drugs that reduce protein carbonylation can effectively prevent tissue damage and neurological deficits. We envision that in the future these agents could be administered in combination with antioxidants, anti-inflammatory or neuroactive substances for an improved clinical management of chronic MS.

描述（由申请人提供）：我们的长期目标是定义和表征多发性硬化症（人类中枢神经系统最常见的脱髓鞘疾病）组织损伤的机制。近年来，氧化应激与多发性硬化及其动物模型实验性变态反应性脑脊髓炎（EAE）的病理生理学有关。活性氧（ROS）由活化的巨噬细胞/小胶质细胞释放，或由神经细胞中功能失调的线粒体内源性产生。虽然有不容置疑的实验证据表明，氧化应激在这些疾病中起着因果作用，但ROS产生组织损伤的确切机制尚不清楚。ROS积累的一个主要结果是醛或酮非酶促引入蛋白质的特定氨基酸残基（即羰基化）。基于最近的报告，蛋白质羰基化在其他系统中的分子和细胞的后果和一些重要的发现，从我们的实验室，我们假设氧化应激在EAE的主要结果是羰基化的神经元蛋白，这有助于组织损伤和轴突损伤。我们还提出了抑制蛋白质羰基化将治疗这种疾病的想法。为了检验我们的假设，我们将测量缓解/复发EAE小鼠的脊髓和脑中蛋白质羰基的水平，其与疾病的明确病理标志（炎症、神经元死亡、轴突损伤和脱髓鞘）的关系。这些研究将采用最先进的生物化学和免疫细胞化学技术。然后，我们将通过氧化还原蛋白质组学鉴定疾病炎症和退行性阶段的氧化蛋白质，并从产生的羰基化氨基酸残基类型中确定氧化物质的化学性质和来源。最后，我们将研究各种羰基清除剂和代谢抑制剂，以防止组织损伤和轴突损伤的EAE动物的能力。如果成功，这些研究将揭示一种新的分子机制，氧化应激导致脱髓鞘疾病的慢性残疾。多发性硬化症（MS）是一种神经系统疾病，在美国大约每700名年轻人中就有1人受到影响。我们最近观察到，一种特殊类型的氧化过程称为羰基化修饰MS患者的几种脑蛋白。这些修饰影响蛋白质功能，并可能导致这种毁灭性疾病的组织损伤。使用MS小鼠模型，我们将确定减少蛋白质羰基化的药物是否可以有效地防止组织损伤和神经功能缺损。我们设想，在未来，这些药物可以与抗氧化剂，抗炎或神经活性物质联合使用，以改善慢性MS的临床管理。