Jae Won Oh, Seong Joon Ahn, Jae Hun Jung, Tae Wan Kim, Kwang Pyo Kim
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引用次数: 0
Abstract
Diabetic retinopathy (DR) is a leading cause of blindness in adults under 40 in the developed world, with a significant proportion progressing to vision-threatening stages such as proliferative diabetic retinopathy (PDR) and neovascular glaucoma (NVG). This study aims to explore the molecular mechanisms underlying the progression from non-proliferative DR (NPDR) to PDR and NVG, focusing on identifying potential biomarkers and therapeutic targets. Utilizing discovery-based proteomics, specifically label-free quantification (LFQ) and Tandem mass tag (TMT), we analyzed aqueous humor (AH) proteins obtained during cataract surgery or anterior chamber paracentesis from patients with NPDR, PDR, and NVG. Validation of marker candidates for each disease state was conducted using triple quadrupole (QQQ)-MS for targeted protein quantification. Our proteomic analysis identified 2,255 proteins and gene ontology analysis and functional annotation highlighted key biological processes implicated in DR, such as lens development, immune responses and lipid metabolism. Validation of potential biomarkers identified 20 proteins with significant concentration changes, including several candidates with diagnostic utility based on ROC curve analysis. Further investigation into clinical relevance revealed that crystallin gamma-S (CRYGS) is strongly associated with cataract severity, highlighting its role as a potential marker for ocular complications in DR. Importantly, we identified that the pathological factors driving DR progression have a much greater impact than age, a previously known variable, in shaping the proteomic landscape of aqueous humor. Additionally, proteins associated with macular degeneration (CA1, CA2, and HBA1) were uncovered, providing new insights into overlapping mechanisms between DR and other retinal diseases. Finally, proteins linked to panretinal photocoagulation (PRP) treatment, including APOB and CST6, were identified, suggesting their involvement in the therapeutic response and post-treatment adaptation. These findings underscore the potential of AH proteomics in uncovering predictive biomarkers and elucidating the molecular pathogenesis of DR and its complications.
糖尿病视网膜病变（DR）是发达国家40岁以下成年人失明的主要原因，其中很大一部分进展为视力威胁阶段，如增殖性糖尿病视网膜病变（PDR）和新生血管性青光眼（NVG）。本研究旨在探讨非增殖性DR （NPDR）向PDR和NVG发展的分子机制，重点寻找潜在的生物标志物和治疗靶点。利用基于发现的蛋白质组学，特别是无标记定量（LFQ）和串联质量标签（TMT），我们分析了NPDR、PDR和NVG患者在白内障手术或前房穿刺术中获得的房水（AH）蛋白。采用三重四极杆(QQQ)-质谱法对每种疾病状态的候选标记物进行验证，用于靶向蛋白定量。我们的蛋白质组学分析鉴定了2255个蛋白质，基因本体分析和功能注释强调了DR中涉及的关键生物过程，如晶状体发育、免疫反应和脂质代谢。潜在生物标志物的验证鉴定了20种具有显著浓度变化的蛋白质，其中包括几种基于ROC曲线分析具有诊断效用的候选蛋白质。进一步的临床相关性研究表明，晶体蛋白γ - s （CRYGS）与白内障严重程度密切相关，突出了其作为DR眼部并发症潜在标志物的作用。重要的是，我们发现，在形成房水蛋白质组学景观方面，驱动DR进展的病理因素比年龄（一个先前已知的变量）的影响要大得多。此外，与黄斑变性相关的蛋白（CA1、CA2和HBA1）被发现，为DR和其他视网膜疾病之间的重叠机制提供了新的见解。最后，研究人员发现了与全视网膜光凝（PRP）治疗相关的蛋白，包括APOB和CST6，表明它们参与了治疗反应和治疗后适应。这些发现强调了AH蛋白质组学在发现预测性生物标志物和阐明DR及其并发症的分子发病机制方面的潜力。
期刊介绍：
The mission of MCP is to foster the development and applications of proteomics in both basic and translational research. MCP will publish manuscripts that report significant new biological or clinical discoveries underpinned by proteomic observations across all kingdoms of life. Manuscripts must define the biological roles played by the proteins investigated or their mechanisms of action.
The journal also emphasizes articles that describe innovative new computational methods and technological advancements that will enable future discoveries. Manuscripts describing such approaches do not have to include a solution to a biological problem, but must demonstrate that the technology works as described, is reproducible and is appropriate to uncover yet unknown protein/proteome function or properties using relevant model systems or publicly available data.
Scope:
-Fundamental studies in biology, including integrative "omics" studies, that provide mechanistic insights
-Novel experimental and computational technologies
-Proteogenomic data integration and analysis that enable greater understanding of physiology and disease processes
-Pathway and network analyses of signaling that focus on the roles of post-translational modifications
-Studies of proteome dynamics and quality controls, and their roles in disease
-Studies of evolutionary processes effecting proteome dynamics, quality and regulation
-Chemical proteomics, including mechanisms of drug action
-Proteomics of the immune system and antigen presentation/recognition
-Microbiome proteomics, host-microbe and host-pathogen interactions, and their roles in health and disease
-Clinical and translational studies of human diseases
-Metabolomics to understand functional connections between genes, proteins and phenotypes
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