PROTEIN CARBONYLATION AND AXONAL DAMAGE IN EAE

EAE 中的蛋白质羧化和轴突损伤

• 批准号: 7795735
• 负责人: OSCAR A BIZZOZERO
• 金额: $ 26.73万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795735
• 关键词: Active Immunization; Acute; Affect; Aldehydes; Amines; Amino Acids; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Arts; 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; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Experimental Designs; Female; Functional disorder; Future; Goals; Histidine; Human; Hydralazine; Hydrazine; Hydrazines; Impairment; Inflammation; Inflammatory; Injury; Ketones; Laboratories; Lead; Lesion; Measures; Metabolic; Metabolic Pathway; 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; public health relevance; research study; therapeutic development; young adult

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(申请人提供)：我们的长期目标是定义和描述多发性硬化症潜在的组织损伤机制，多发性硬化症是人类最常见的中枢神经系统脱髓鞘疾病。近年来，氧化应激与多发性硬化症及其动物模型实验性变态反应性脑脊髓炎(EAE)的病理生理机制有关。活性氧(ROS)是由激活的巨噬细胞/小胶质细胞释放的，或由神经细胞中功能失调的线粒体内源性产生的。尽管有毋庸置疑的实验证据表明氧化应激在这些疾病中起到了因果作用，但ROS导致组织损伤的确切机制(S)还远不清楚。ROS积累的一个主要结果是将醛或酮以非酶方式引入蛋白质的特定氨基酸残基(即羰化)。根据最近关于蛋白质在其他系统中的分子和细胞后果的报道以及我们实验室的一些重要发现，我们假设EAE中氧化应激的一个主要结果是神经元蛋白质的羰化，这是导致组织损伤和轴突损伤的原因。我们还提出了抑制蛋白质羰化对这种疾病有治疗作用的观点。为了验证我们的假设，我们将测量缓解/复发EAE小鼠脊髓和大脑中蛋白质羰基的水平与疾病公认的病理特征(炎症、神经元死亡、轴突损伤和脱髓鞘)的关系。这些研究将使用最先进的生化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化阶段的氧化蛋白质，并从产生的羰基氨基酸残基类型确定氧化物种的化学性质和来源。最后，我们将检查各种羰基清除剂和代谢抑制剂预防EAE动物组织损伤和轴突损伤的能力。如果成功，这些研究将揭示一种新的分子机制，即氧化应激导致脱髓鞘障碍的慢性残疾。公共卫生相关性：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，称为羰化作用，可以修饰多发性硬化症患者的几种大脑蛋白质。这些修饰会影响蛋白质的功能，并可能导致这种毁灭性疾病的组织损伤。利用多发性硬化症的小鼠模型，我们将确定减少蛋白质羰化的药物是否可以有效地防止组织损伤和神经缺陷。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一起使用，以改善慢性MS的临床治疗。