Matrix metalloproteinases as biomarkers of neurodegeneration

描述(由申请人提供)：神经退行性疾病影响着超过5000万美国人，每年造成超过5000亿美元的损失。已经做出了相当大的努力来确定神经退变的生物标志物，这将使得能够对与病程(类型0)纵向相关的神经退行性疾病进行早期和具体的诊断；用于评估神经保护干预的有效性(类型1)，或用于预测临床结果(类型2，或替代终点)。基质金属蛋白酶(MMPs)是一类细胞外蛋白，作为脱髓鞘、免疫细胞迁移和血脑通透性的调节因子，与多种神经退行性疾病有关。最近的一系列报告表明，MMPs是多发性硬化症、中风和阿尔茨海默病的生物标记物。我们自己对周围神经系统的初步研究表明，基质金属蛋白酶，特别是基质金属蛋白酶-9，显示出一种高度敏感、特异和早期的周围神经退行性变生物标志物的关键属性。通过建立Weller ain变性的MMP9基因敲除模型，结合MMP9的中和治疗，我们已经建立了MMP9水平与周围神经损伤后巨噬细胞内流、髓鞘降解和神经胶质细胞激活之间的直接联系。这些神经退变的特征将使我们能够比较评估MMPs和其他MMPs作为大鼠周围神经(坐骨神经和L5脊神经)和中枢(L5脊髓)神经退变的生物标志物的价值。MMPs作为脊髓损伤的替代生物标志物的有效性将通过使用不同药物类别的药物(如利鲁唑、地佐西平、米诺环素)进行实验性神经保护治疗来评估。这项建议的总体目标是系统地评估MMPs作为中枢和/或周围神经退行性变的生物标志物的价值，这些标志物可能对神经退行性疾病的诊断、临床前或临床评估有用。基质金属蛋白(MMPs)是一类控制细胞外间隙结构分子如胶原蛋白、细胞表面受体、细胞黏附分子和其他蛋白质降解的蛋白酶家族。我们的研究证实了MMPs在周围神经退行性变、免疫细胞募集和神经病理性疼痛中的重要作用。基质金属蛋白酶-9显示了一个特别重要的特征：它的活性是退行性疾病所特有的，在任何明显的损伤表现之前，它的强劲和早期的增加在组织和体液中很容易被量化。本研究旨在确定MMPs作为神经退行性疾病生物标志物的价值，可用于神经退行性疾病的早期诊断和神经保护治疗对脊髓损伤的疗效。

DESCRIPTION (provided by applicant): Neurodegenerative disorders affect over 50 millions of Americans and cost annually over 500 billion dollars. Considerable efforts have been put forth to identifying biomarkers of neurodegeneration, that will allow for early and specific diagnosis of neurodenerative conditions that correlate longitudinally with the course of the disease (type 0); for evaluation of the effectiveness of neuroprotective intervention (type 1), or for predicting the clinical outcome (type 2, or surrogate endpoint). Matrix Metalloproteinases (MMPs) are the family of extracellular proteases that have been associated with many neurodegenerative disorders as modulators of demyelination, immune cell migration and blood-brain permeability. A series of recent reports have implicated MMPs as biomarkers of multiple sclerosis, stroke and Alzheimer's disease. Our own preliminary studies in the peripheral nervous system demonstrate that MMPs, particularly MMP-9, display critical attributes of a highly sensitive, specific and early biomarker of peripheral neurodegeneration. Using MMP-9 gene knockout model of Wallerain degeneration, and MMP-9-neutralizing therapy, we have established a direct link between MMP-9 levels and macrophage influx, myelin degradation and glial activation after peripheral nerve injury. These features of neurodegeneration will allow us to comparatively assess the value of MMP-9 and other MMPs as biomarkers of peripheral (sciatic nerve and L5 spinal nerve) and central (L5 spinal cord) neurodegeneration in rat. The utility of MMPs as surrogate biomarkers for spinal cord injury will be evaluated using experimental neuroprotective therapy with agents of different drug classes (i.e. riluzole, dizocilpine, minocycline). The overall goal of this proposal is to systematically evaluate the value of MMPs as biomarkers of central and/or peripheral neurodegeneration potentially useful for diagnostic, preclinical or clinical assessments in neurodegenerative conditions. Matrix Metalloproteainses (MMPs) is a protease family that controls degradation of structural molecules, such as collagens, cell surface receptor, cell adhesion molecules and other proteins of the extracellular spaces. Our studies demonstrate the important role of MMPs in peripheral neurodegeneration, immune cell recruitment and neuropathic pain. MMP-9 displays a particularly important feature: its activity is specific to degenerative conditions and its robust and early increase is readily quantifiable in tissues and body fluids, before any visible manifestation of injury. This proposal aims to determine the value of MMPs as biomarkers of neurodegeneration that could be used for the early diagnosis of neurodegenerative disease and the efficacy of neuroprotective therapy to spinal cord injury.