Matrix metalloproteinases as biomarkers of neurodegeneration

神经退行性疾病影响超过5000万美国人，每年花费超过5000亿美元。已经做出了相当大的努力来鉴定神经变性的生物标志物，其将允许早期和特异性诊断与疾病过程纵向相关的神经变性病症（0型）;用于评估神经保护干预的有效性（1型），或用于预测临床结果（2型，或替代终点）。基质金属蛋白酶（MMP）是细胞外蛋白酶家族，其作为脱髓鞘、免疫细胞迁移和血脑渗透性的调节剂与许多神经退行性疾病相关。最近的一系列报道暗示MMPs是多发性硬化、中风和阿尔茨海默病的生物标志物。我们自己在周围神经系统中的初步研究表明，MMP，特别是MMP-9，显示出周围神经变性的高度敏感，特异性和早期生物标志物的关键属性。使用MMP-9基因敲除Wallerain变性模型和MMP-9中和治疗，我们已经建立了周围神经损伤后MMP-9水平与巨噬细胞内流、髓鞘降解和胶质细胞活化之间的直接联系。神经变性的这些特征将使我们能够比较评估MMP-9和其他MMP作为大鼠外周（坐骨神经和L5脊神经）和中枢（L5脊髓）神经变性的生物标志物的价值。将使用不同药物类别的药物（即利鲁唑、地佐环平、米诺环素）进行实验性神经保护治疗，评价MMP作为脊髓损伤替代生物标志物的效用。本提案的总体目标是系统地评价MMPs作为中枢和/或外周神经变性生物标志物的价值，其可能用于神经变性疾病的诊断、临床前或临床评估。基质金属蛋白酶（MMP）是一种蛋白酶家族，其控制结构分子如胶原、细胞表面受体、细胞粘附分子和细胞外间隙的其它蛋白质的降解。我们的研究表明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。MMP-9显示出特别重要的功能：其活性对退行性疾病是特异性的，并且在任何可见的损伤表现之前，其在组织和体液中的稳健和早期增加是容易量化的。本研究旨在探讨MMPs作为神经退行性疾病生物标志物的价值，为神经退行性疾病的早期诊断和脊髓损伤的神经保护治疗提供依据。

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.