外周血和尿液中粘多糖贮积症Ⅱ型早期蛋白标志物的研究

Mucopolysaccharidosis type II (MPS II) is a X-linked recessive mucopolysaccharide disease and is also known as Hunter syndrome. The average lifespan of patients with attenuated form of MPS II is less than 22 years, and that of severe form is no more than 12 years. It is well known that early detection and treatment are critical in optimizing patient outcomes and could result in greater clinical benefit. However, most medical staff lacks the necessary experience to diagnose MPS II due to its rarity. Moreover, researches those focusing on its pathologic mechanisms and diagnosis methods are still limited up until now because of the insufficient public awareness. Therefore, its clinical manifestation varies and the misdiagnosis or missed diagnosis was a common occurrence. The shortage of effective diagnostic methods, especially for the newborn, is the main cause of failure in MPS II patient identification during the early stage, thus the best therapeutic period were often missed as the result.Our previous studies have shown that peptides and proteins from the urine of MPS II patients have the distinct pattern than that of health individuals. In this research, we aim to investigate the finding further by extensively comparing the protein profile of peripheral blood and urine using differential proteomic methods. Furthermore, comprehensive assessment will be conducted in order to obtain a number of candidate proteins as the potential biomarkers for MPS II diagnosis and the panel will be validated for its sensitivity and specificity. The result of this study may improve our understanding of the progression of MPS II, lay the foundation for accurate early diagnosis and treatment, and provide new strategy for newborn screening.

粘多糖贮积症Ⅱ型（Mucopolysaccharidosis type II，MPS II）又称Hunter 综合征，是一种X连锁隐性遗传的MPS。患者寿命仅为一、二十岁。MPS II属于罕见病，大多数医务人员缺乏对该病的诊断经验；同时由于社会重视程度不够，对该病的病因和诊断研究较少，现有的诊断方法常会造成该病的误诊和漏诊，使患者错失疾病治疗的最佳时期。基于我们前期研究发现，MPS II患者尿液与正常人相比存在着差异多肽和蛋白，本研究拟在此基础上运用比较蛋白质组学方法，分别从外周血和尿液两种来源的样本中探索与MPS II相关的差异蛋白，并综合两种来源的差异蛋白的变化规律找出具有潜在的MPS II标志物组，进一步进行临床验证，研究其准确度和灵敏度。同时分析其在MPS II发生过程中的作用，为发展新的MPS II早期精准诊断和治疗技术奠定基础，并为实现MPS II的新生儿筛查提供新的思路。

粘多糖贮积症Ⅱ型（Mucopolysaccharidosis type II，MPS II），是由于降解粘多糖所需的IDS缺陷，致使体内大量粘多糖贮积的一种遗传代谢性疾病。主要表现为特殊面容、生长迟缓、骨骼畸形、脏器受累和进行性智力低下，危害十分严重。由于早期诊断的不及时，会造成患者的发育、神经、生理的不可逆改变。因此，亟需简单可靠的诊断方法辅助早期诊断。本研究以尿液为研究对象，采用标记定量蛋白质组学的方法，探索与MPS II相关的差异蛋白。同时，对MPS的另一种类型—MPS Ⅰ，进行蛋白质组学分析。iTRAQ联合LC-MS/MS尿液差异蛋白分析结果显示，Ⅰ型中共鉴定出849种差异蛋白，涉及最多的是代谢通路；Ⅱ型共鉴定出693种差异蛋白，涉及最多的是剪接体和核糖体；Western Blot结果显示LUM和DCN含量在Ⅰ型、Ⅱ型尿液中含量均降低。TMT联合LC-MS/MS尿液差异蛋白分析结果显示，Ⅰ型共鉴定出262种差异蛋白，涉及最多的是肿瘤通路，Ⅱ型共鉴定出202种差异蛋白，涉及最多的是补体和凝血系统通路；PRM个体验证结果显示，HEXB、CSTB在MPS Ⅰ尿液中含量增多，DHRS2在Ⅰ型、Ⅱ型尿液中含量均降低。TMT联合LC-MS/MS对Ⅰ型血浆分析结果显示，共鉴定出123种差异蛋白，涉及最多的通路是吞噬体通路；PRM个体验证结果显示LAMP2、SPP2在MPS Ⅰ血浆中含量增多，PLG、APOA1、APOC1、IGFBP3在MPS Ⅰ血浆中含量降低。综上所述，本研究通过分析尿液中与MPS Ⅱ相关的差异蛋白质组，筛选疾病生物标志物，帮助疾病早期诊断；构建蛋白网络，寻找MPS Ⅱ 所影响的信号通路，为致病机制的阐明提供研究依据。同时，对MPSⅠ进行血液和尿液的蛋白质组学分析，为MPS Ⅱ进一步研究提供参考。

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