Endovascular Health and Platelet Activity in Psoriasis

银屑病的血管内健康和血小板活性

• 批准号: 10352405
• 负责人: Michael Seth Garshick
• 金额: $ 17.36万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10352405
• 关键词: Address; Adhesions; Affect; Age; American; Atherosclerosis; Biological; Biology; Blood Platelets; Blood Vessels; Cardiac; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion; Chronic; Clinical; Cross-Sectional Studies; Data; Dermatology; Development; Disease; Effector Cell; Endothelial Cells; Endothelium; Ethnic Origin; Event; Exhibits; Foundations; Future; Genes; Goals; Harvest; Health; Human; Immunology; Impairment; In Vitro; Incubated; Inflammasome; Inflammation; Inflammatory; Intercellular adhesion molecule 1; Interleukin-1 beta; Interleukin-17; Interleukin-6; Interleukin-8; Investigation; Joints; Laboratories; Lead; Measures; Mediating; Methodology; Methods; Modality; Myocardial Infarction; New York; P-Selectin; Pathogenesis; Pathway interactions; Patients; Physiologic pulse; Platelet Activation; Platelet aggregation; Populations at Risk; Production; Proteins; Psoriasis; Publishing; Race; Randomized Clinical Trials; Recurrence; Reporting; Research; Research Design; Rheumatology; Risk; Role; Serum; Severities; Severity of illness; Signal Pathway; Signal Transduction; Skin; TNF gene; Techniques; Testing; Therapeutic Intervention; Transcript; United States National Institutes of Health; Universities; Vascular Endothelium; Veins; Venous; Whole Blood; brachial artery; cardiovascular disorder risk; cardiovascular risk factor; career development; chronic inflammatory skin; clinical development; collaborative environment; cytokine; differential expression; illness length; immune activation; in vivo; inflammatory marker; innovation; mortality; overexpression; platelet function; platelet phenotype; randomized trial; recruit; sex; skin disorder; systemic inflammatory response; targeted treatment; therapeutic target; transcriptome sequencing; translational scientist; vascular endothelial dysfunction

PROJECT SUMMARY/ABSTRACT Background: Psoriasis is a common chronic inflammatory skin disease associated with an ~50% increased risk of cardiovascular disease (CVD) compared to matched controls. The influence of psoriasis-related systemic inflammation on vascular health and subsequent cardiovascular (CV) risk is not fully known. Vascular endothelial dysfunction, activated platelets, and the interaction between the two are instrumental to the pathogenesis of atherosclerosis. As a way to understand mechanisms of increased CV risk in psoriasis, this study will test the overarching hypothesis that the vascular endothelium in psoriasis is inflamed, dysfunctional, and contributes to CVD development as assessed by endovascular and platelet phenotyping, and that platelets from patients with psoriasis act as effector cells promoting impaired vascular health. To develop therapeutic targets to reduce CV risk, mechanism(s) that lead to the development of clinical CVD must be clarified. Preliminary Data: Our group has shown using direct brachial vein endothelial cell analysis, that patients with psoriasis exhibit impaired vascular endothelial health. Furthermore, unbiased analysis highlights inflammasome (IL-1β) signaling with downstream IL-6 protein production as the highest differentially expressed systemic pathway in psoriasis and correlated with impaired endothelial vascular health. Our preliminary data also reveal that patients with psoriasis overexpress P-selectin (a marker of platelet activation), directly activate cultured human aortic endothelial cells in vitro, and that markers of platelet activation correlate with serum IL-6 levels. This suggests that platelets contribute to the impaired vascular health we observe in psoriasis. These findings have clinical implications because randomized clinical trials targeting the inflammasome pathway (with a corresponding circulating IL-6 reduction) in patients with established CVD reduced cardiac events. Methods: We will recruit 100 psoriasis and 50 healthy age-, sex-, race/ethnicity matched controls across the spectrum of psoriatic disease and various treatment modalities to explore: (1) Vascular health in vivo by flow- mediated brachial artery reactivity testing and pulse wave velocity studies, and directly ex vivo via analysis of endothelial cells obtained from brachial veins; (2) Platelet biology through investigations into platelet reactivity, platelet aggregation, and the platelets ability to activate endothelial cells in vitro. Objectives and Career Development: No study has shown that targeting psoriatic disease activity reduces the development of CVD. This proposal uses a highly collaborative environment between experts in CV and platelet biology, immunology, dermatology, and rheumatology. It will lay the groundwork to propose future larger-scale studies designed to reduce CV risk in patients with psoriasis. Furthermore, it will allow the PI to become an expert in pro-inflammatory conditions, refine innovative methodologies and laboratory techniques to study mechanisms of subclinical CVD, and provide a framework to become an independent clinical- translational investigator.

项目摘要/摘要 背景：牛皮癣是一种常见的慢性炎性皮肤病，风险增加约50％ 与匹配的对照相比，心血管疾病（CVD）的疾病（CVD）。牛皮癣相关的全身性的影响 血管健康和随后的心血管（CV）风险的炎症尚不清楚。血管内皮 功能障碍，活化的血小板以及两者之间的相互作用对 动脉粥样硬化。作为了解牛皮癣CV风险增加机制的一种方式，本研究将测试 总体假设是牛皮癣中的血管内皮发炎，功能失调，并有助于 通过血管内和血小板表型评估的CVD发育，以及来自患者的血小板 牛皮癣是促进血管健康受损的效应细胞。开发治疗目标以减少CV 必须阐明导致临床CVD发展的风险，机制。 初步数据：我们的小组使用直接臂静脉内皮细胞分析表明，患有 牛皮癣暴露于血管内皮健康受损。此外，无偏分析突出显示 炎性体（IL-1β）具有下游IL-6蛋白产生的信号传导，作为最高差异表达的 牛皮癣的全身途径，与内皮血管健康受损相关。我们的初步数据 还表明牛皮癣患者过表达P-选择素（血小板激活的标记），直接激活 培养的人主动脉内皮细胞体外，血小板激活的标记与血清IL-6相关 水平。这表明血小板有助于我们在牛皮癣中观察到的血管健康受损。这些 研究结果具有临床意义，因为针对炎症途径的随机临床试验（带有 确定的CVD降低心脏事件的患者中相应的循环IL-6降低）。 方法：我们将招募100个牛皮癣和50个健康年龄 - 性别，种族/种族匹配的控制 银屑病疾病的光谱和各种治疗方式要探索：（1）流量的血管健康在体内 通过分析 从肱静脉获得的内皮细胞； （2）通过研究血小板反应性的血小板生物学， 血小板聚集和血小板在体外激活内皮细胞的能力。 目标和职业发展：没有研究表明，靶向银屑病活动会减少 CVD的发展。该提案使用简历专家之间的高度协作环境 血小板生物学，免疫学，皮肤病学和风湿病学。它将为提议未来提供基础 大规模研究旨在降低牛皮癣患者的简历风险。此外，它将允许PI 成为促炎条件，完善创新方法和实验室技术的专家 研究亚临床CVD的机制，并提供了一个框架，使其成为独立的临床 - 翻译调查员。