Platelet Activity and Vascular Health in Systemic Lupus Erythematosus

系统性红斑狼疮的血小板活性和血管健康

• 批准号: 10304126
• 负责人: Jeffrey S Berger
• 金额: $ 76.4万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304126
• 关键词: Address; Adhesives; Adrenal Cortex Hormones; Age; Antiphospholipid Antibodies; Atherosclerosis; Autoantibodies; Autoimmune Diseases; Biological; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell physiology; Cessation of life; Cholesterol; Clinical; Clinical Research; Code; Complex; Cross-Sectional Studies; Cytomegalovirus Infections; Data; Diabetes Mellitus; Diagnostic; Diagnostic tests; Disease; Dyslipidemias; Effector Cell; Endothelial Cells; Endothelium; Enrollment; Ethnic Origin; Evaluation; Event; Flare; Functional disorder; Gene Expression; Gene Expression Profile; Genetic Transcription; Health; Heterogeneity; Human Cell Line; Hyperactivity; Hypertension; Impairment; In Vitro; Incubated; Individual; Inflammation; Inflammatory; Knowledge; Laboratories; Leukocytes; Life; Light; Measurement; Measures; Mediating; Mediator of activation protein; Metabolic; Microvascular Dysfunction; Molecular; Musculoskeletal Diseases; Myocardial Infarction; Nephritis; Non-Steroidal Anti-Inflammatory Agents; Organ; Outcome; Pathologic; Pathway interactions; Patient Representative; Patients; Phenotype; Phospholipids; Play; Process; Publishing; RNA; Race; Regulation; Reproducibility; Risk; Risk Factors; Role; Serositis; Severities; Signal Transduction; Smoking; Smooth Muscle Myocytes; Systemic Lupus Erythematosus; Testing; Thrombosis; Time; Transcript; Translations; Untranslated RNA; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Vascular Smooth Muscle; atherogenesis; atherothrombosis; brachial artery; cardiovascular disorder risk; cardiovascular risk factor; cell type; chemokine; clinical phenotype; comorbidity; cytokine; disorder control; ds-DNA; endothelial dysfunction; follow-up; high risk; immune activation; improved; in vitro activity; in vivo; indexing; insight; macrophage; minimal risk; modifiable risk; monocyte; mortality; novel; novel diagnostics; patient subsets; platelet function; platelet phenotype; premature; premature atherosclerosis; prevent; recruit; risk stratification; sex; skin disorder; therapeutic target; thrombogenesis; transcriptome; transcriptomics; vascular injury

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.

项目摘要/摘要 系统性红斑狼疮 (SLE) 是一种复杂的自身免疫性疾病，给治疗带来了多种挑战 临床医生，包括表现的异质性、起伏的病程以及显着升高的风险 血管功能障碍和过早心血管疾病。传统风险因素的能力有限 区分 SLE 患者的心血管风险。血小板，包含转录本和 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剂， 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 和单核细胞产生炎症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。血小板作为血管生成的相关贡献者已被充分研究 SLE 的功能障碍和过早心血管疾病。 我们提出了一组补充研究，以全面评估血小板在患者中的机制作用 患有系统性红斑狼疮。该系列研究将包括血小板活性测量、编码和非编码 RNA 概况、血小板作为体外调节内皮细胞和白细胞活性的效应细胞，以及 使用肱动脉反应性测试测量体内血管健康状况。提议的方法 将包括对 200 名 SLE 患者进行的横断面研究，以涵盖器官受累的全部范围 疾病活动。我们还将招募 50 名年龄、性别和种族/民族相匹配的疾病对照者。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 受疾病活动度和临床表型的显着影响，（2）SLE血小板会诱发炎症， 内皮细胞中的血栓形成和粘附基因表达以及随后的反应性， 单核细胞/巨噬细胞和血管平滑肌细胞，以及 (3) SLE 血小板表型和 转录组与血管功能受损显着相关。 50年纵向随访 代表活动期和静止期疾病的患者将使我们能够确定生物制剂是否 读数跟踪特定的患者子集以及读数是否随时间变化。 这项研究将提供新的数据，以解决有关该协会的现有知识差距 血小板活性测量、血小板转录组和作为效应细胞的血小板之间 SLE 整个临床范围内的血管健康。这项研究将确定是否存在独特的 血小板活性增加和/或血管健康受损的 SLE 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 患者血管功能障碍风险增加，并且 通过研究潜在的可改变的危险因素来治疗心血管疾病。这些数据应提供 深入了解调节 SLE 血小板活性的分子机制，新的风险诊断测试 分层和治疗目标以改善临床结果。

项目成果

Platelet and Vascular Biomarkers Associate With Thrombosis and Death in Coronavirus Disease.

血小板和血管生物标志物与冠状病毒疾病中的血栓形成和死亡相关。

• 发表时间: 2020
• 影响因子: 20.1
• 作者: Barrett, Tessa J;Lee, Angela H;Xia, Yuhe;Lin, Lawrence H;Black, Margaret;Cotzia, Paolo;Hochman, Judith;Berger, Jeffrey S
• 通讯作者: Berger, Jeffrey S

Platelet regulation of myeloid suppressor of cytokine signaling 3 accelerates atherosclerosis.

血小板对细胞因子信号传导 3 的骨髓抑制因子的调节会加速动脉粥样硬化。

• 发表时间: 2019
• 影响因子: 17.1
• 作者: Barrett, Tessa J;Schlegel, Martin;Zhou, Feli;Gorenchtein, Mike;Bolstorff, Jennifer;Moore, Kathryn J;Fisher, Edward A;Berger, Jeffrey S
• 通讯作者: Berger, Jeffrey S

Perioperative Cardiovascular Risk Assessment and Management for Noncardiac Surgery: A Review.

非心脏手术围手术期心血管风险评估和管理：综述。

• 发表时间: 2020
• 作者: Smilowitz, Nathaniel R;Berger, Jeffrey S
• 通讯作者: Berger, Jeffrey S

Human low-affinity IgG receptor FcγRIIA polymorphism H131R associates with subclinical atherosclerosis and increased platelet activity in systemic lupus erythematosus.

人类低亲和力 IgG 受体 FcγRIIA 多态性 H131R 与亚临床动脉粥样硬化和系统性红斑狼疮血小板活性增加有关。

• 发表时间: 2019-03
• 作者: Clancy, Robert;El Bannoudi, Hanane;Rasmussen, Sara E;Bornkamp, Nicole;Allen, Nicole;Dann, Rebecca;Reynolds, Harmony;Buyon, Jill P;Berger, Jeffrey S
• 通讯作者: Berger, Jeffrey S

Modeling of clinical phenotypes in systemic lupus erythematosus based on the platelet transcriptome and FCGR2a genotype.

基于血小板转录组和 FCGR2a 基因型的系统性红斑狼疮临床表型建模。

• 发表时间: 2023-04-07
• 作者: Cornwell, MacIntosh G;Bannoudi, Hanane El;Luttrell;Engel, Alexis;Barrett, Tessa J;Myndzar, Khrystyna;Izmirly, Peter;Belmont, H Michael;Clancy, Robert;Ruggles, Kelly V;Buyon, Jill P;Berger, Jeffrey S
• 通讯作者: Berger, Jeffrey S