The pathogenic role of protein aggregation in inflammatory demyelination

蛋白质聚集在炎症脱髓鞘中的致病作用

• 批准号: 8658497
• 负责人: OSCAR A BIZZOZERO
• 金额: $ 18.69万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658497
• 关键词: Active Immunization; Acute; Affect; Animal Model; Apoptosis; Biochemical; Brain; C57BL/6 Mouse; Cell Death; Cells; Central Nervous System Diseases; Chronic; Clinical Management; Complex; Data; Demyelinating Diseases; Demyelinations; Development; Disease; Excision; Experimental Autoimmune Encephalomyelitis; Experimental Designs; Female; Functional disorder; Glutathione; Goals; Human; Impairment; Inflammation; Inflammatory; Injury; Laboratories; Lead; Lesion; Link; Molecular; Multiple Sclerosis; Mus; Necrosis; Neurodegenerative Disorders; Neurologic; Neurons; Oligodendroglia; Oxidative Stress; Patients; Pattern; Peptides; Pharmaceutical Preparations; Play; Post-Translational Protein Processing; Process; Proteins; Role; Series; Spinal Cord; Symptoms; Techniques; Testing; Tissues; Treatment Efficacy; Work; axonal degeneration; base; central nervous system demyelinating disorder; crosslink; cytotoxic; design; improved; inhibitor/antagonist; mouse model; multicatalytic endopeptidase complex; nervous system disorder; neuron loss; novel; novel therapeutics; oxidation; polypeptide; prevent; prophylactic; protein aggregate; protein aggregation; protein misfolding; public health relevance; research study; young adult

DESCRIPTION (provided by applicant): Our long-term goal is to define and characterize the mechanisms underlying tissue injury in multiple sclerosis (MS), 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 MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Previous studies from our laboratory have shown that MS and EAE, like several other neurological disorders, are characterized by the accumulation of carbonylated (oxidized) proteins within CNS cells. We have also demonstrated that the build-up of oxidized and other misfolded proteins in these disorders is a consequence of decreased activity of the proteasome, the proteolytic machinery responsible for their removal. Carbonylation and other oxidative protein modifications are known to cause inappropriate inter- and intra-protein cross-links as well as protein misfolding. This, in turn, results in the formation of protein aggregates that we believe contribute to the demise of neural cells and ultimately tissue damage. Indeed, we have obtained preliminary evidence that aggregates containing oxidized proteins accumulate in the CNS of MS patients and EAE mice and that inhibition of protein aggregation prevents neuronal cell death in culture. Based on these novel findings, we hypothesize that protein aggregation plays a pathogenic role in EAE. To test this idea, we will (1) quantify the temporal/spatial pattern of protein aggregation and its relationship to the extent of neuronal and oligodendroglial cell death in the spinal cord during the course of MOG peptide-induced EAE, and (2) examine the prophylactic and therapeutic efficacy of two chemically- distinct protein aggregation inhibitors at preventing cell death and tissue injury and at reducing neurological symptoms of EAE. If successful, these studies will not only demonstrate that protein aggregation is pathogenic in inflammatory demyelinating disease but also will provide the basis for developing new or testing previously identified non-toxic aggregation inhibitors for an improved clinical management of 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（MS）组织损伤的机制，MS是人类中枢神经系统最常见的脱髓鞘疾病。近年来，氧化应激已被牵连在MS及其动物模型，实验性自身免疫性脑脊髓炎（EAE）的病理生理学。我们实验室以前的研究表明，MS和EAE与其他几种神经系统疾病一样，其特征在于CNS细胞内羰基化（氧化）蛋白质的积累。我们还证明，在这些疾病中氧化和其他错误折叠的蛋白质的积累是蛋白酶体活性降低的结果，蛋白酶体是负责去除它们的蛋白水解机制。已知羰基化和其他氧化蛋白质修饰会导致蛋白质间和蛋白质内不适当的交联以及蛋白质错误折叠。这反过来又导致蛋白质聚集体的形成，我们认为这有助于神经细胞的死亡和最终的组织损伤。事实上，我们已经获得了初步的证据，含有氧化蛋白质的聚集体积累在MS患者和EAE小鼠的CNS中，并且抑制蛋白质聚集可以防止培养中的神经元细胞死亡。基于这些新的发现，我们假设蛋白质聚集在EAE中起致病作用。为了测试这个想法，我们将（1）量化蛋白质聚集的时间/空间模式及其与MOG肽诱导的EAE过程中脊髓中神经元和少突胶质细胞死亡程度的关系，和（2）检查两种化学上不同的蛋白质聚集抑制剂在预防细胞死亡和组织损伤以及在减少EAE的神经症状方面的预防和治疗功效。如果成功，这些研究将不仅证明蛋白质聚集在炎性脱髓鞘疾病中是致病性的，而且还将为开发新的或测试先前确定的无毒聚集抑制剂以改善MS的临床管理提供基础。