EHD1-mediated Inflammation and Resolution in Atherosclerosis

EHD1 介导的动脉粥样硬化炎症和消退

• 批准号: 10568133
• 负责人: Bishuang Cai
• 金额: $ 72.08万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568133
• 关键词: Address; Affect; Anti-Inflammatory Agents; Apoptotic; Area; Arterial Fatty Streak; Atherosclerosis; Autophagocytosis; C-terminal; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell physiology; Cell surface; Cells; Cholesterol; Chronic; Clinical; Data; Disease; Enzymes; Event; Gene Expression; Goals; Human; Human Genetics; Immune response; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Integral Membrane Protein; Interruption; Lesion; Link; Lipids; Lipoproteins; Macrophage; Mediating; Mediator; Membrane; Metalloproteases; Mus; Myelogenous; Necrosis; Pathway interactions; Persons; Phenotype; Play; Population; Positioning Attribute; Process; Protein Family; Protein Tyrosine Kinase; Proteins; Recycling; Research; Research Personnel; Residual state; Resolution; Risk; Role; Testing; Therapeutic; atherosclerotic plaque rupture; cardiovascular risk factor; cell type; cytokine; driving force; human disease; infection risk; inhibition of autophagy; lipid mediator; novel; novel therapeutic intervention; prevent; receptor; retrograde transport; selective expression; single-cell RNA sequencing; sortilin; tissue repair; trafficking; transcriptome sequencing; Address; Affect; Anti-Inflammatory Agents; Apoptotic; Area; Arterial Fatty Streak; Atherosclerosis; Autophagocytosis; C-terminal; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell physiology; Cell surface; Cells; Cholesterol; Chronic; Clinical; Data; Disease; Enzymes; Event; Gene Expression; Goals; Human; Human Genetics; Immune response; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Integral Membrane Protein; Interruption; Lesion; Link; Lipids; Lipoproteins; Macrophage; Mediating; Mediator; Membrane; Metalloproteases; Mus; Myelogenous; Necrosis; Pathway interactions; Persons; Phenotype; Play; Population; Positioning Attribute; Process; Protein Family; Protein Tyrosine Kinase; Proteins; Recycling; Research; Research Personnel; Residual state; Resolution; Risk; Role; Testing; Therapeutic; atherosclerotic plaque rupture; cardiovascular risk factor; cell type; cytokine; driving force; human disease; infection risk; inhibition of autophagy; lipid mediator; novel; novel therapeutic intervention; prevent; receptor; retrograde transport; selective expression; single-cell RNA sequencing; sortilin; tissue repair; trafficking; transcriptome sequencing

Project Summary/Abstract Atherosclerotic cardiovascular disease (CVD), a chronic lipoprotein-driven inflammatory disorder, is the leading cause of death worldwide. Conventional lipid-lowering therapies only modestly lower cardiovascular risk in the population due to “residual risk,” thought to be caused by excessive inflammation. Emerging evidence shows that the interruption of inflammation resolution, an active tissue repair process, is a key mechanism that contributes to atherosclerotic plaque progression. Therefore, identifying novel targets that mediate both inflammation and resolution is crucial for developing cardiovascular therapeutic strategies that can both boost resolution and prevent inflammation. As endocytic trafficking is an essential cellular process that regulates macrophage function, we have focused on the role of C-terminal Eps15 homology domain-containing (EHD) family proteins, the key conductors of endocytic trafficking in the immune response of macrophages. The publicly available single-cell RNA sequencing (scRNA-seq) data of macrophage populations in both human and murine atherosclerotic plaques reveal that EHD1 is selectively expressed in inflammatory lesional macrophages compared with other EHD proteins, and our new study shows that EHD1 levels are increased in lesional macrophages from both human and murine plaques as atherosclerosis progresses. These data support an overall proatherogenic role for EHD1 and underscore its relevance to human disease. The overall objective of this proposal is to study the role and the underlying mechanisms of EHD1 in inflammation and resolution in the context of atherosclerosis. Our data suggest that EHD1 impairs inflammation resolution by inducing the ectodomain cleavage of MerTK, an efferocytosis receptor required for timely resolution of inflammation, and aids inflammation by promoting macrophage polarization toward a proinflammatory phenotype. Moreover, we have established a novel link between EHD1 and sortilin, a human genetic risk factor for CVD, by showing that EHD1 silencing decreases sortilin protein levels. The ectodomain of MerTK is cleaved by the metalloproteinase ADAM17, and our preliminary data show that EHD1 enhances ADAM17 on the cell surface, where shedding takes place. Hence, we will test our hypothesis that EHD1 promotes ADAM17 recycling to the cell surface, which leads to MerTK cleavage, defective efferocytosis, impaired inflammation resolution, and plaque necrosis (Aim 1). As autophagy is well known to suppress polarization of proinflammatory macrophages and we found that EHD1 suppresses autophagy, we hypothesize that EHD1 promotes proinflammatory macrophage polarization by suppressing autophagy, leading to inflammatory plaque progression (Aim 2). Finally, we will investigate whether EHD1 stabilizes sortilin and induces inflammatory cytokine secretion by facilitating retrograde transport of sortilin (Aim 3). By exploring the role of EHD1 in atherosclerosis, we hope to bring to the forefront an important new concept regarding EHD1-mediated intracellular trafficking in plaque progression, one that could provide the basis for novel therapeutic strategies to prevent CVD.

项目摘要/摘要 动脉粥样硬化心血管疾病（CVD）是一种慢性脂蛋白驱动疾病，是领先的 全球死亡原因。常规降低脂质疗法仅适度较低的心血管风险 由于“残留风险”而导致的人口是由过度炎症引起的。新兴证据表明 炎症分辨率的中断（一种有效的组织修复过程）是一种关键机制， 有助于动脉粥样硬化斑块的进展。因此，确定介导的新目标 炎症和分辨率对于发展心血管治疗策略至关重要，这些策略既可以提高 分辨率并防止注射。由于内吞运输是一种调节的必不可少的细胞过程 巨噬细胞函数，我们专注于C端EPS15同源域（EHD）的作用 家族蛋白，巨噬细胞免疫反应中内吞运输的主要导体。公开 人和鼠类中巨噬细胞种群的可用单细胞RNA测序（SCRNA-SEQ）数据 动脉粥样硬化斑块表明，EHD1在炎症性巨噬细胞中有选择地表达 与其他EHD蛋白相比，我们的新研究表明，病变中的EHD1水平有所增加 随着动脉粥样硬化的进展，人类和鼠斑块的巨噬细胞都在进行。这些数据支持 EHD1的总体促进作用，并强调了其与人类疾病的相关性。总体目标 该建议是研究EHD1在炎症和解决中的作用和潜在机制 动脉粥样硬化的背景。我们的数据表明，EHD1损害了通过诱导的注射分辨率 MERTK的外生域裂解，及时分辨炎症所需的feROCOLOCYOCYOPOLOCYOPOLOCYOCYOSOS受体和AIDS 通过促进巨噬细胞极化向促炎表型进行炎症。而且，我们有 通过证明EHD1，建立了EHD1和Tortilin之间的新型联系，这是CVD的人类遗传危险因素 沉默降低了排序蛋白蛋白水平。 MERTK的外部域被金属蛋白酶裂解 ADAM17，我们的初步数据表明，EHD1在细胞表面上增强了ADAM17，在那里脱落 发生。因此，我们将检验我们的假设，即EHD1促进了ADAM17回收到细胞表面， 导致MERTK裂解，有缺陷的肿瘤病，注射分辨率受损和斑块坏死（AIM 1）。由于自噬众所周知可以抑制促炎性巨噬细胞的极化，我们发现 EHD1抑制自噬，我们假设EHD1促进了促炎巨噬细胞极化 通过抑制自噬，导致炎症斑块进展（AIM 2）。最后，我们将调查 EHD1是否通过支持逆行转运来稳定托丝蛋白并诱导炎症性细胞因子分泌 Tortilin（AIM 3）。通过探索EHD1在动脉粥样硬化中的作用，我们希望将其带到最前沿 关于EHD1介导的细胞内贩运的新概念，可以提供 预防CVD的新型治疗策略的基础。