Platelet Activity and Vascular Health in Systemic Lupus Erythematosus

项目摘要/摘要 系统性红斑狼疮是一种复杂的自身免疫性疾病，对 临床医生，包括临床表现的异质性，病程起伏，以及显著增加的 血管功能障碍和过早的心血管疾病。传统的风险因素在能力上是有限的 鉴别系统性红斑狼疮患者的心血管风险。血小板，其中包含转录和 进行翻译所必需的分子机制，是动脉粥样硬化血栓形成的细胞间调节因子， 血管功能障碍、炎症和免疫激活。活化的血小板可诱导内皮细胞 和单核细胞产生炎性细胞因子和趋化因子，导致血管损伤和 随后的动脉粥样硬化形成。作为血管的相关贡献者，血小板的研究还不够深入。 系统性红斑狼疮患者的功能障碍和早产儿心血管疾病。 我们提出了一组补充研究，以充分评估患者中血小板的机制作用。 系统性红斑狼疮。这一系列研究将包括血小板活性测量、编码和非编码RNA 在体外，血小板作为调节内皮细胞和白细胞活性的效应细胞 用臂动脉反应性试验测量活体血管健康。建议的方法 将包括对200名系统性红斑狼疮患者的横断面研究，涵盖器官受累的全部范围和 疾病活动。我们还将招募50名年龄、性别和种族/民族匹配的疾病控制人员。这项研究 假设(1)血小板活性测量和血小板衍生的编码和非编码RNA是 受疾病活动性和临床表型的显著影响，(2)SLE血小板可诱发炎症， 血管内皮细胞中血栓形成和黏附基因的表达及随后的反应性 单核/巨噬细胞和血管平滑肌细胞；(3)SLE血小板表型和 转录组与血管功能受损密切相关。纵向随访50例 同时代表活动期和静止期疾病的患者将使我们能够确定生物 读数跟踪特定的患者子集，以及读数是否随着时间的推移而变化。 这项研究将提供新的数据来解决关于这种联系的现有知识差距 在血小板活性测量之间，血小板转录组和作为效应细胞的血小板 系统性红斑狼疮临床范围内的血管健康状况。这项研究将确定是否有一个独特的 血小板活性升高和/或血管健康受损的系统性红斑狼疮患者的血小板RNA表达谱 从这项研究中获得的数据将确定SLE患者血管功能障碍和 通过研究一种潜在的可改变的危险因素来预防心血管疾病。这些数据应该能提供 对SLE中调节血小板活性的分子机制的洞察--新的风险诊断测试 分层，以及改善临床结果的治疗目标。

PROJECTSUMMARY/ABSTRACT Systemic lupus erythematosus (SLE) is a complex autoimmune disease that poses several challenges to the clinician, including heterogeneity of presentation, undulating course, and a significantly elevated risk for vascular dysfunction and premature cardiovascular disease. Traditional risk factors are limited in their ability to discriminate cardiovascular risk in patients with SLE. Platelets, which contain transcripts and the necessary molecular machinery to conduct translation, are intercellular regulators of atherothrombosis, vascular dysfunction, inflammation, and immune activation. Activated platelets can induce endothelial cells and monocytes to produce inflammatory cytokines and chemokines resulting in vascular injury and subsequent atherogenesis. Platelets have been understudied as a relevant contributor to vascular dysfunction and premature cardiovascular disease in SLE. We propose a complementary set of studies to fully evaluate the mechanistic role of platelets in patients with SLE. The array of studies will include platelet activity measurements, coding and non-coding RNA profiles, platelets as effector cells regulating endothelial cell and leukocyte activity in vitro, and measurement of vascular health in vivo using brachial artery reactivity testing. The proposed approach will include a cross sectional study of 200 SLE patients to cover the full spectrum of organ involvement and disease activity. We will also enroll 50 age- sex- and race/ethnicity- matched disease controls. The study hypotheses are that (1) platelet activity measurements and platelet-derived coding and noncoding RNA are significantly influenced by disease activity and clinical phenotype, (2) SLE platelets will induce inflammatory, thrombogenic, and adhesive gene expression and consequent reactivity in endothelial cells, monocytes/macrophages, and vascular smooth muscle cells, and (3) SLE platelet phenotype and transcriptome will significantly associate with impaired vascular function. Longitudinal follow-up in 50 patients representative of both active and quiescent disease will allow us to ascertain whether biologic readouts track with a specific subset of patients and whether the readouts change over time. This study will provide novel data to address existing gaps in knowledge regarding the association between platelet activity measurements, the platelet transcriptome, and platelets as effector cells and vascular health across the clinical spectrum of SLE. This study will ascertain whether there is a unique platelet RNA expression profile in SLE with increased platelet activity and/or with impaired vascular health. Data obtained from this study will identify SLE patients at increased risk for vascular dysfunction and cardiovascular disease by investigating a potentially modifiable risk factor. These data should provide insight into the molecular mechanisms regulating platelet activity in SLE, novel diagnostic tests for risk stratification, and therapeutic targets to improve clinical outcomes.