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ENGLISH ABSTRACT
剥脱综合征患者房水蛋白质组学分析
徐钊
王礼明
冯强
张丹丹
阿依古再丽
郭如如
东莉洁
魏瑞华
刘爱华
作者及单位信息
·
DOI： 10.3760/cma.j.cn115989-20221101-00509
Proteomic analysis of aqueous humor in patients with exfoliation syndrome
Xu Zhao
Wang Liming
Feng Qiang
Zhang Dandan
Ayiguzaili Tuerdimaimaiti
Guo Ruru
Dong Lijie
Wei Ruihua
Liu Aihua
Authors Info & Affiliations
Xu Zhao
Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China
Wang Liming
Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China
Feng Qiang
Department of Ophthalmology, People's Hospital of Hotan District, Hotan Perfecture 848000, China
Zhang Dandan
Department of Ophthalmology, People's Hospital of Hotan District, Hotan Perfecture 848000, China
Ayiguzaili Tuerdimaimaiti
Department of Ophthalmology, People's Hospital of Hotan District, Hotan Perfecture 848000, China
Guo Ruru
Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China
Dong Lijie
Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China
Wei Ruihua
Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China
Liu Aihua
Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China
·
DOI： 10.3760/cma.j.cn115989-20221101-00509
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摘要

目的分析剥脱综合征(XFS)患者房水蛋白质的表达差异。

方法收集2020年6月至2021年1月在和田地区人民医院拟行手术治疗的维吾尔族年龄相关性白内障患者和XFS伴白内障患者各10例，分别作为白内障组和XFS组。术中借助超声乳化手术通道吸取前房中部50～100 μl房水。通过非标记定量蛋白质组学质谱分析技术对房水中提取的蛋白进行分析，以白内障组作为对照组，并根据 P<0.05、差异倍数>1.5的标准筛选得到XFS组的差异表达蛋白。通过基因本体论(GO)功能分析和京都基因与基因组百科全书(KEGG)信号通路分析来探讨XFS组差异表达蛋白的功能及调控信号通路。

结果与白内障组相比，XFS组共鉴定出25个差异表达蛋白，这些蛋白主要涉及细胞黏附、受体、水解酶、分子运输等。表达下调的蛋白有14个，包括补体H因子相关蛋白1(CFHR1)、内质网分子伴侣BiP(HSPA5)、双糖链蛋白多糖(BGN)、FRAS1相关的细胞外基质蛋白2(FREM2)、血红蛋白亚基δ(HBD)、血红蛋白亚单位γ1(HBG1)、棕榈酰蛋白水解酶2(PPT2)等。表达上调的蛋白有11个，包括转化生长因子结合蛋白2(LTBP2)、极低密度脂蛋白受体、层粘连蛋白亚基α2(LAMA2)、凝血因子Ⅸ(F9)等。其中，FREM2为XFS组差异表达最显著的蛋白，其在XFS组个体样本中表达水平基本一致。GO分析显示，这些差异蛋白主要定位于胶原蛋白的细胞外基质、结合珠蛋白－血红蛋白复合物、血浆脂蛋白颗粒和溶酶体腔；分子功能和生物学过程显示，HBD和HBG1参与细胞解毒过程，PPT2参与水解酶活性，BGN和LTBP2参与糖胺聚糖结合。KEGG信号通路分析显示，CFHR1和F9参与补体和凝血级联通路；FREM2和LAMA2参与细胞外基质相互作用通路。

结论XFS的进展可能与细胞外基质蛋白的改变、血－房水屏障破坏以及潜在的炎症反应有关。显著下调的FREM2可能作为XFS潜在的生物学标志物。

剥脱综合征;房水;蛋白质组学;FRAS1相关的细胞外基质蛋白2;生物学信息分析
ABSTRACT

ObjectiveTo analyze the differential expressions of proteins in aqueous humor in patients with exfoliation syndrome (XFS).

MethodsA total of 20 patients were enrolled in the Department of Ophthalmology, People's Hospital of Hotan District from June 2020 to January 2021, including 10 patients with age-related cataract and 10 XFS patients combined with cataract, which were classified as cataract group and XFS group, respectively.A total of 50 to 100 μl aqueous humor was obtained in the middle of the anterior chamber through the intraoperative phacoemulsification channel.The proteins extracted from aqueous humor were analyzed by label-free quantitative proteomics technology.The cataract group was set as the control group, and the differentially expressed proteins (DEPs) in XFS group were screened according to P<0.05 and fold change >1.5.Gene ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis were used to explore the function and regulatory signaling pathways of DEPs in the XFS group.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Tianjin Medical University Eye Hospital (No.2020KY[L]-21).Written informed consent was obtained from each subject.

ResultsIn comparison with the cataract group, 25 DEPs were identified in the XFS group, primarily involved in cell adhesion, receptor, hydrolase, and molecular transport.Specifically, there were 14 down-regulated proteins including complement factor H-related protein 1 (CFHR1), endoplasmic reticulum chaperone BiP (HSPA5), biglycan (BGN), FRAS1-related extracellular matrix protein 2 (FREM2), hemoglobin subunit delta (HBD), hemoglobin subunit gamma-1 (HBG1), lysosomal thioesterase PPT2 (PPT2) etc., and 11 up-regulated proteins including latent-transforming growth factor beta-binding protein 2 (LTBP2), very low-density lipoprotein receptor (VLDLR), laminin subunit alpha-2 (LAMA2), coagulation factor Ⅸ (F9).Among them, FREM2 was the most significantly differentially expressed protein in XFS group with consistent expression levels across individual samples.GO analysis revealed that these DEPs mainly localized to the extracellular matrix of collagen, bound globin-hemoglobin complex, plasma lipoprotein particles and lysosomes.Molecular functions and biological processes showed that HBD and HBG1 were involved in cellular detoxification, PPT2 in hydrolase activity, and BGN and LTBP2 in glycosaminoglycan binding.KEGG signaling pathway analysis indicated that CFHR1 and F9 were associated with complement and coagulation cascade pathways, and FREM2 and LAMA2 were linked to the extracellular matrix interaction pathway.

ConclusionsDisease progression of XFS may be associated with changes in extracellular matrix proteins, disruption of the blood-aqueous humor barrier, and potential inflammatory responses.The significant down-regulation of FREM2 protein may be a potential biomarker for XFS.

Exfoliation syndrome;Aqueous humor;Proteomics;FRAS1-related extracellular matrix protein 2;Bioinformatics
Liu Aihua, Email: mocdef.6ab216318auhiauil
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引用本文

徐钊,王礼明,冯强,等. 剥脱综合征患者房水蛋白质组学分析[J]. 中华实验眼科杂志,2024,42(06)：512-519.

DOI:10.3760/cma.j.cn115989-20221101-00509

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剥脱综合征(exfoliation syndrome，XFS)是一种年龄相关性疾病，起病隐匿，早期无临床表现，其准确诊断需要有经验的临床医生对患者扩瞳后于裂隙灯显微镜下进行检查，因此，发病率常被严重低估 [ 1 , 2 ]。XFS进展快速，药物治疗预后差，会导致剥脱性青光眼(exfoliative glaucoma，XFG)，加速白内障的发展 [ 3 ]。在中国，香港地区60岁及以上人群XFS的患病率为0.4% [ 4 ]；与此相比，维吾尔族人口中60岁及以上人群的患病率为2.2%，而80岁及以上人群的患病率进一步上升至9.5% [ 5 ]。在新疆地区，许多XFS/XFG患者因缺乏有效诊断和治疗视力受到影响或丧失。因此，寻找易于诊断的生物学标志物并了解该病的病理过程十分必要。根据剥脱物在光学显微镜下的特征以及超微结构，XFS病理特征表现为纤维组织过度生产或分解不足，导致纤维基质在眼内外多种组织中慢性积累、聚集并逐渐沉积，其中显著的部位是晶状体前表面和瞳孔边缘 [ 6 , 7 ]。XFS的全基因组关联研究表明，赖氨酰氧化酶样蛋白1基因编码区的单核苷酸多态性(single nucleotide polymorphism，SNP)以及钙通道基因 CACNA1A的SNP与XFS发生风险有关，并推测这2个基因通过不同机制引起细胞外基质(extracellular matrix，ECM)代谢紊乱，从而参与XFS病理过程 [ 8 , 9 , 10 , 11 , 12 , 13 ]，但基因组研究并不能清楚地解释XFS具体的病理生理机制。相对于基因组学而言，基于质谱的蛋白质组学研究具有整体性和动态性特点。目前，该技术已被广泛应用于生物医药领域 [ 14 , 15 ]，相关研究结果不仅有利于加深对疾病机制的理解，还能够获取新的疾病生物学标志物，并为分子靶向治疗提供新的思路。目前已有不同国家关于XFS相关蛋白质组学研究的报道，研究结果涵盖了细胞生长因子、炎症因子、抗氧化因子、补体蛋白、氧化应激标志物和血液蛋白衍生物的改变，以及基质金属蛋白酶和组织金属蛋白酶抑制剂失调等 [ 16 , 17 , 18 ]。房水对眼压和眼前节微环境的维持至关重要 [ 19 , 20 ]。目前尚未有关于中国XFS患者房水蛋白质组学研究的报道。本研究采用非标记定量蛋白质组学技术，以维吾尔族年龄相关性白内障患者房水的蛋白作为对照组，鉴定维吾尔族XFS患者房水中的差异蛋白，并进行生物信息学分析探讨这些蛋白的改变，以期更好地理解XFS发生的分子机制，并筛选XFS的生物学标志物。
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刘爱华，Email： mocdef.6ab216318auhiauil
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徐钊：直接参与选题、实施研究、收集数据、分析/解释数据、统计学分析、文章撰写及修改；王礼明：收集数据、分析数据、修改文章；冯强：收集样本、分析数据；张丹丹：收集样本、实施研究；阿依古再丽：收集样本、统计分析；郭如如：实施研究、解释数据；东莉洁：酝酿和设计实验、指导研究；魏瑞华：指导实验、文章修改；刘爱华：直接参与选题、酝酿和设计实验、对文章知识性内容的审阅及定稿

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新疆维吾尔自治区自然科学基金面上项目 (2020D01A06)
天津医科大学眼科医院临床研究中心青年专项基金 (2020QN02)
天津市医学重点学科（专科）建设项目 (TJYXZDXK-037A)
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