Total plasma and IgG glycomes, statin therapy and ASCVD events

7.项目摘要/摘要 葡聚糖是在翻译后糖基化的酶过程中连接到蛋白质上的糖。这 蛋白质的翻译后修饰增强了它们的功能异质性，对许多人来说很重要 生物过程。多糖在调节炎症和先天免疫方面发挥着特殊的调节作用。 系统，以及其他已知的促进动脉粥样硬化的关键生理和病理过程。 大多数蛋白质都是糖基化的，包括炎症蛋白和免疫球蛋白G，含量最高 循环中的免疫球蛋白。这些蛋白和其他循环中的糖基化蛋白形成血浆糖蛋白。还没有 对糖基化在ASCVD发生和治疗中的作用的功能了解只有 最近才出现的。糖组学和糖科学已经落后于蛋白质组学和其他“组学”， 尤其是对于心血管应用，其中缺乏对 葡聚糖在动脉粥样硬化中发挥作用。然而，目前高通量糖组学技术的最新进展 可准确识别和定量人体血浆中循环蛋白上的不同糖链。 在这次竞争性的R01更新中，我们建议利用在第一个资助期设立的研究设计， 使用两项嵌套的病例对照研究，其中血管、脂肪和炎性生物标记物的表型很深 综合评估血浆总蛋白和免疫球蛋白G与ASCVD风险的关系。这个 这项研究的目的是通过鉴定糖基化来促进我们对人类糖类的理解 与ASCVD事件和风险因素，特别是炎症性因素正相关或负相关的模式 和血管危险因素。此外，针对蛋白质糖基化或蛋白质糖基化的新心血管疗法 炎症将被添加到他汀类药物的治疗之上，然而评估他汀类药物对蛋白质影响的研究 糖基化作用很少。为了阐明这些重要的问题，我们将进行两个预期的案例- 对照研究(1,050对配对病例对照)，利用基线研究和对照研究的可用性 第一年的血液样本，用于重复测量多糖和血管危险因素。拟议的研究将 评估从两种血浆总蛋白中分离出的促炎和抗炎多糖的综合小组 和免疫球蛋白G，检查与血管生物标记物、危险因素和临床事件以及 评估他汀类药物如何调节糖链的平衡。建议的研究将以下列费用完成： 有效和高效的设计，因为可以获得来自第一个奖项的广泛的表型数据 周而复始。这一综合方法利用糖组学技术的最新进展来阐明特定的 促炎和抗炎多聚糖具有推动该领域发展和开发创新多聚糖的潜力 与精确心血管医学相一致的靶向生物标志物或潜在的治疗方法。

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.