Total plasma and IgG glycomes, statin therapy and ASCVD events

7.项目概要/摘要 聚糖是在翻译后糖基化的酶促过程中与蛋白质连接的糖。这 蛋白质的翻译后修饰增强了它们的功能异质性， 生物过程。聚糖在调节炎症（先天免疫）方面发挥特定的调节作用 系统以及已知促进动脉粥样硬化的其他关键生理和病理过程。 大多数蛋白质都是糖基化的，包括炎症蛋白和最丰富的免疫球蛋白G 免疫球蛋白循环。这些和其他循环糖基化蛋白质形成血浆糖组。然而 对糖基化在ASCVD发展和治疗中的作用的功能性理解， 最近出现的。糖组学和糖科学已经落后于蛋白质组学和其他“组学”， 特别是对于心血管应用，其中缺乏对整体作用的理解， 聚糖在动脉粥样硬化中起作用。然而，目前高通量糖组学技术的最新进展 允许准确鉴定和定量人血浆中循环蛋白上的不同聚糖。 在本次竞争性R 01更新中，我们建议利用第一个资助期内建立的研究设计， 使用两项嵌套病例对照研究，对血管、脂质和炎症生物标志物进行深入表型分析， 综合评价总血浆和免疫球蛋白G糖组与ASCVD风险的关系。的 本研究的目的是通过鉴定糖基化， 与ASCVD事件和风险因素（特别是炎症）正相关或负相关的模式 和血管危险因素。此外，靶向蛋白质糖基化或 炎症将被添加到他汀类药物治疗的基础上，但评估他汀类药物对蛋白质的影响的研究 糖基化很少。为了阐明这些重要问题，我们将进行两个前瞻性案例- 对照研究（1，050个匹配的病例对照对）利用基线研究和 第1年血液样本，用于重复测量聚糖和血管风险因素。拟定的研究将 评价从两种总血浆蛋白中分离的一组全面的促炎和抗炎聚糖 和免疫球蛋白G，与血管生物标志物、风险因素和临床事件相关，以及 评估他汀类药物如何调节聚糖的平衡。这项拟议的研究将在一个成本完成- 有效和高效的设计，因为从该奖项的第一个广泛的表型数据的可用性 周期这种综合方法利用糖组学技术的最新进展来阐明特定的 促炎和抗炎聚糖具有推进该领域并开发基于聚糖的创新药物的潜力。 靶向生物标志物或潜在的治疗方法符合精确的心血管医学。

7. Project Summary/Abstract Glycans are sugars attached to proteins in the enzymatic process of post-translational glycosylation. This post-translational modification of proteins enhances their functional heterogeneity and is important for many biological processes. Glycans play specific regulatory roles in modulating inflammation, the innate immune system, and other key physiological and pathological processes that are known to promote atherosclerosis. Most proteins are glycosylated, including inflammatory proteins and immunoglobulin G, the most abundant immunoglobulin in circulation. These and other circulating glycosylated proteins form the plasma glycome. Yet functional understanding of the role of glycosylation in ASCVD development and therapeutics has only recently emerged. Glycomics and glycosciences have lagged behind proteomics and other “omics”, in particular for cardiovascular applications where there is a deficiency in understanding the integral role that glycans play in atherosclerosis. However, recent advances in high-throughput glycomics technologies now allow the accurate identification and quantification of distinct glycans on circulating proteins in human plasma. In this competing R01 renewal, we propose to leverage the study design set up in the first funding period, using two nested case-control studies with deeply phenotyped vascular, lipid, and inflammatory biomarkers, to comprehensively evaluate the total plasma and immunoglobulin G glycomes in relation to ASCVD risk. The goal of this study is to advance our understanding of the human glycome by identifying glycosylation patterns related positively or inversely to incident ASCVD and risk factors, in particular inflammatory and vascular risk factors. Furthermore, new cardiovascular therapies targeting protein glycosylation or inflammation will be added on top of statin therapy, yet studies evaluating the impact of statins on protein glycosylation are scarce. To elucidate these important questions, we will conduct two prospective case- control studies (1,050 matched case-control pairs) leveraging the availability in both studies of baseline and year 1 blood samples for repeat measurements of glycans and vascular risk factors. The proposed study will evaluate a comprehensive panel of pro- and anti-inflammatory glycans isolated from both total plasma proteins and immunoglobulin G, examined in relation to vascular biomarkers, risk factors, and clinical events, as well as assess how statins modulate the balance of glycans. The proposed study will be accomplished in a cost- effective and efficient design because of the availability of the extensive phenotypic data from the award’s first cycle. This comprehensive approach utilizing recent advances in glycomics technologies to elucidate specific pro-and anti-inflammatory glycans has the potential to advance the field and develop innovative glycan-based targeted biomarkers or potential therapeutic approaches in line with precision cardiovascular medicine.