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.

项目概要和摘要 尽管有标准的护理，动脉粥样硬化性心血管疾病 (CVD) 仍然是发病的主要原因 和美国的死亡率。尽管充分控制了心血管疾病，但近一半患者的 CVD 风险仍升高 标准风险因素。在这一组中，炎症被认为是一个关键驱动因素。尽管有这样的见解，但没有针对性 CVD 存在抗炎疗法。因此，迫切需要阐明新的机制。 动脉粥样硬化的慢性炎症。我实验室的长期目标是了解增强剂如何 可塑性通过影响改变细胞状态的基因表达来驱动动脉粥样硬化。总体目标 该提案的目的是 1) 阐明血管内皮细胞 (EC) 的炎症激活如何改变 EC 2) 定义 BRD4 在动脉粥样硬化形成中 EC 激活中的作用。我们的中心假设是 细胞因子和促动脉粥样硬化脂质的长期炎症激活可指导持久的重塑 增强子使得基底细胞状态丢失并激活新的炎症细胞状态。我们的假设是 根据我们之前发表的工作以及新的初步数据制定，这些数据揭示了以下内容： i) 人类主动脉 EC (HAEC) 的慢性炎症刺激导致部分 新的超级增强剂； ii) 在 HAEC 中，尽管去除了促炎细胞，这些新的增强子区域仍然存在 刺激； iii) 核心转录因子 (TF) 电路可以从序列特异性 TF 基序推断出来，这些基序是 富含慢性炎症超级增强剂； iv) BRD4 抑制可阻止腹膜炎中白细胞的募集 动脉粥样硬化形成部分是通过 EC 效应实现的。该项目的基本原理是为了更深入地了解 慢性炎症的分子介质有望确定新的药物靶点 逆转导致动脉粥样硬化的血管细胞的长期病理性激活。为了实现我们的整体 为了实现目标，我们将追求以下综合但不相互依赖的具体目标： 1) 确定如何 慢性促动脉粥样硬化刺激重塑染色质结构并揭示人类动脉 EC 的新增强子 2) 确定 Brd4 在体内动脉粥样硬化形成过程中维持 EC 状态的功能作用。整体 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细胞 通过持续增强子激活的细胞状态。该提案的核心创新在于概念上的转变 研究范式通过证明炎症通过动态驱动动脉粥样硬化的病理细胞状态 染色质结构、增强子功能和基因表达之间的相互作用。