Elucidating the chromatin-dependent mechanisms governing chronic inflammatory activation of endothelial cells in atherosclerosis.

阐明控制动脉粥样硬化中内皮细胞慢性炎症激活的染色质依赖性机制。

• 批准号: 10363671
• 负责人: JONATHAN David BROWN
• 金额: $ 58.64万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10363671
• 关键词: Acute; Animals; Anti-Inflammatory Agents; Architecture; Atherosclerosis; Automobile Driving; Basal Cell; Biological Assay; Blood Vessels; Cardiovascular Diseases; Cells; Chromatin; Chromatin Structure; Chronic; Coupled; Cytokine Activation; Data; Disease; Endothelial Cells; Engineering; Enhancers; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Growth; Health; Histones; Human; Inflammation; Inflammatory; Inflammatory Response; Knock-out; Laboratories; Leukocytes; Lipids; Maps; Mediator of activation protein; Medical Research; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; Nodal; Outcome; Pathologic; Pathology; Pathway interactions; Patient risk; Patients; Peritonitis; Proteins; Public Health; Publishing; RNA Polymerase II; Reporter; Research; Residual state; Risk Factors; Role; Seminal; Signal Transduction; Stimulus; Testing; United States; United States National Institutes of Health; Vascular Endothelial Cell; Work; atherogenesis; atherosclerosis risk; burden of illness; cardiovascular disorder risk; chromatin remodeling; design; disability; gene regulatory network; genome-wide; improved; in vivo; innovation; insight; loss of function; mortality; new therapeutic target; novel; novel therapeutic intervention; recruit; response; standard of care; transcription factor

Project Summary and Abstract Despite standard of care, atherosclerotic cardiovascular disease (CVD) remains a leading cause of morbidity and mortality in the United States. In nearly half of patients, risk of CVD is elevated despite adequate control of standard risk factors. In this group, inflammation is proposed as a key driver. Despite this insight, no targeted anti-inflammatory therapies exist for CVD. Thus, an urgent unmet need exists to elucidate novel mechanisms of chronic inflammation in athersclerosis. The long-term goal of my laboratory is to understand how enhancer plasticity drives atherosclerosis through effects on gene expression that change cell state. The overall objectives of this proposal are to 1) to elucidate how inflammatory activation of vascular endothelial cells (ECs) alters EC identity and 2) to define the role of BRD4 in EC activation in atherogenesis. Our central hypothesis is that prolonged inflammatory activation by cytokines and proatherogenic lipids directs a durable remodeling of enhancers such that basal cell state is lost and a new inflammatory cell state is activated. Our hypothesis is formulated on the basis of our previously published work as well as new preliminary data that reveal the following: i) chronic inflammatory stimulation of human aortic ECs (HAECs) results in dynamic activation of a subset of new super enhancers; ii) in HAECs, these new enhancer regions persist despite removing the proinflammatory stimulus; iii) a core transcription factor (TF) circuitry can be inferred from sequence-specific TF motifs that are enriched at chronic inflammatory super enhancers; iv) BRD4 inhibition blocks leukocyte recruitment in peritonitis and atherogenesis in part through EC effects. The rationale for this project is that a deeper understanding of the molecular mediators of chronic inflammation holds the promise of identifying new drug targets designed to reverse the long-term, pathologic activation of vascular cells that drives atherosclerosis. To achieve our overall objectives, we will pursue the following integrated, but non-interdependent specific aims: 1) To determine how chronic, proatherogenic stimuli remodel chromatin structure and unveil new enhancers in human arterial ECs and 2) To determine the functional role of Brd4 in maintaining EC state during atherogenesis in vivo. The overall contribution of this work will be to elucidate how chronic inflammatory signaling establishes a new endothelial cell state through persistent enhancer activation. The central innovation of this proposal is a conceptual shift in research paradigm by demonstrating inflammation drives pathologic cell states in atherosclerosis by a dynamic interplay between chromatin structure, enhancer function and gene expression.

项目摘要和摘要 尽管有护理标准，但动脉粥样硬化心血管疾病（CVD）仍然是发病率的主要原因 和在美国的死亡率。在近一半的患者中，尽管有足够的控制 标准风险因素。在这一组中，提出了炎症为关键驱动力。尽管有这种见解，但没有针对性 CVD存在抗炎疗法。因此，存在紧急未满足的需求，以阐明 静止性炎症。我实验室的长期目标是了解增强器 可塑性通过改变细胞状态的基因表达来促进动脉粥样硬化。总体目标 该提议为1）阐明血管内皮细胞（ECS）的炎症激活如何改变EC 身份和2）定义BRD4在EC激活中的作用。我们的中心假设是 细胞因子和促性脂质长期激活的炎症激活指导耐用的重塑 增强子使基底细胞态丢失并激活新的炎症细胞状态。我们的假设是 根据我们先前发表的工作以及新的初步数据制定的，这些数据揭示了以下内容： i）人主动脉ECS（HAEC）的慢性炎症刺激导致动态激活的动态激活 新的超级增强剂； ii）在HAEC中，尽管消除了促炎性，但这些新的增强子地区仍然存在 刺激； iii）核心转录因子（TF）电路可以从序列特异性TF基序中推断 富含慢性炎症超级增强剂； iv）BRD4抑制阻滞腹膜炎中的白细胞募集 和动脉粥样硬化部分通过EC效应。该项目的理由是对 慢性炎症的分子介质具有识别旨在的新药物靶标 扭转驱动动脉粥样硬化的血管细胞的长期病理激活。为了实现我们的整体 目标，我们将追求以下整合但非相关的特定目的：1）确定如何确定 人动脉EC中的慢性，促进性刺激的重塑染色质结构和新增强剂 2）确定BRD4在体内动脉粥样硬化期间维持EC态的功能作用。总体 这项工作的贡献将是阐明慢性炎症信号如何建立新的内皮 通过持续增强子激活通过细胞状态。该提议的核心创新是概念上的转变 通过证明炎症驱动动态性动脉粥样硬化的病理细胞态来研究范式 染色质结构，增强子功能和基因表达之间的相互作用。