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.

项目概要/摘要 系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病， 临床医生，包括表现的异质性，起伏的过程，和显着升高的风险， 血管功能障碍和早发心血管疾病。传统的风险因素在其能力有限， 鉴别SLE患者的心血管风险。其中包括文字记录和 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， 随后动脉粥样硬化形成。血小板作为一种血管性疾病的相关因素尚未得到充分研究。 功能障碍和早发心血管疾病。 我们提出了一组补充研究，以充分评估血小板在患者中的机制作用。 关于SLE一系列研究将包括血小板活性测量，编码和非编码RNA 血小板作为效应细胞在体外调节内皮细胞和白细胞活性， 使用肱动脉反应性测试测量体内血管健康。所提出的方法 将包括200例SLE患者的横断面研究，以涵盖器官受累的全谱， 疾病活动。我们还将招募50名年龄、性别和种族/民族匹配的疾病对照。研究 假设是：（1）血小板活性测量和血小板衍生的编码和非编码RNA， 受疾病活动性和临床表型的显著影响，（2）SLE血小板可诱导炎症反应， 血栓形成和粘附基因表达以及随后的内皮细胞反应性， 单核细胞/巨噬细胞和血管平滑肌细胞，和（3）SLE血小板表型和 转录组将与受损的血管功能显著相关。纵向随访50例 活动期和静止期疾病的代表性患者将使我们能够确定生物学 读数跟踪患者的特定子集以及读数是否随时间改变。 这项研究将提供新的数据，以解决现有的知识差距， 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的关系， 血管健康在SLE的临床谱。这项研究将确定是否有一个独特的 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血管功能障碍风险增加的SLE患者， 通过调查潜在的可改变的风险因素来研究心血管疾病。这些数据应该提供 深入了解调节SLE血小板活性的分子机制，新的风险诊断试验 分层和治疗目标，以改善临床结果。

项目成果

Cardiovascular Risk in Patients With Psoriasis: JACC Review Topic of the Week.

• DOI: 10.1016/j.jacc.2021.02.009
• 发表时间: 2021-04-06
• 期刊: Journal of the American College of Cardiology
• 影响因子: 24
• 作者: Garshick MS;Ward NL;Krueger JG;Berger JS
• 通讯作者: Berger JS

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

• DOI: 10.1186/s12967-023-04059-w
• 发表时间: 2023-04-07
• 期刊: JOURNAL OF TRANSLATIONAL MEDICINE
• 影响因子: 7.4
• 作者: Cornwell, MacIntosh G.;El Bannoudi, Hanane;Luttrell-Williams, Elliot;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.

Evaluation of SARS-CoV-2 IgG antibody reactivity in patients with systemic lupus erythematosus: analysis of a multi-racial and multi-ethnic cohort.

• DOI: 10.1016/s2665-9913(21)00114-4
• 发表时间: 2021-08
• 期刊: The Lancet. Rheumatology
• 作者: Saxena A;Guttmann A;Masson M;Kim MY;Haberman RH;Castillo R;Scher JU;Deonaraine KK;Engel AJ;Belmont HM;Blazer AD;Buyon JP;Fernandez-Ruiz R;Izmirly PM;NYU WARCOV Investigators
• 通讯作者: NYU WARCOV Investigators

Prevalence and Outcomes of D-Dimer Elevation in Hospitalized Patients With COVID-19.

• DOI: 10.1161/atvbaha.120.314872
• 发表时间: 2020-10
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Berger JS;Kunichoff D;Adhikari S;Ahuja T;Amoroso N;Aphinyanaphongs Y;Cao M;Goldenberg R;Hindenburg A;Horowitz J;Parnia S;Petrilli C;Reynolds H;Simon E;Slater J;Yaghi S;Yuriditsky E;Hochman J;Horwitz LI
• 通讯作者: Horwitz LI

Aspirin for Primary Prevention-Time to Rethink Our Approach.

• DOI: 10.1001/jamanetworkopen.2022.10144
• 发表时间: 2022-04-01
• 期刊: JAMA NETWORK OPEN
• 影响因子: 13.8
• 作者: Berger, Jeffrey S.