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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

基本信息

批准号：
8564373
负责人：
OSCAR A BIZZOZERO
金额：
$ 22.65万
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：
2013
资助国家：
美国
起止时间：
2013-05-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8564373
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

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 (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描述多发性硬化症（MS）组织损伤的机制，多发性硬化症是人类中枢神经系统最常见的脱髓鞘疾病。近年来，氧化应激被认为与MS及其动物模型实验性自身免疫性脑脊髓炎（EAE）的病理生理有关。我们实验室之前的研究表明，MS和EAE，像其他几种神经系统疾病一样，其特征是CNS细胞内羰基化（氧化）蛋白的积累。我们还证明，在这些疾病中，氧化蛋白质和其他错误折叠蛋白质的积累是蛋白酶体活性降低的结果，蛋白酶体是负责清除它们的蛋白质水解机制。已知羰基化和其他氧化蛋白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。反过来，这导致了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证据，表明含有氧化蛋白的聚集体在MS患者和EAE小鼠的中枢神经系统中积累，并且抑制蛋白质聚集可以防止培养中的神经元细胞死亡。基于这些新发现，我们假设蛋白质聚集在EAE中起致病作用。为了验证这一观点，我们将(1)在MOG肽诱导的EAE过程中，量化蛋白质聚集的时间/空间模式及其与脊髓神经元和少突胶质细胞死亡程度的关系，(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减轻EAE神经症状方面的预防和治疗效果。如果成功，这些研究不仅将证明蛋白质聚集在炎症性脱髓鞘疾病中是致病的，而且将为开发新的或测试先前确定的无毒聚集抑制剂提供基础，以改善MS的临床管理。