JMJD3 Regulates Abdominal Aortic Aneurysm Expansion

JMJD3 调节腹主动脉瘤扩张

• 批准号: 10374155
• 负责人: Katherine Ann Gallagher
• 金额: $ 55.79万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374155
• 关键词: Abdominal Aortic Aneurysm; Aneurysm; Animal Model; Anti-Inflammatory Agents; Aortic Aneurysm; Aortic Rupture; Blood Vessels; Cell model; Cells; Cessation of life; Chromatin; Chronic; Clinical; Data; Development; Disease; Enzymes; Epigenetic Process; Exhibits; Failure; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Growth; Homeostasis; Human; Immune; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Interferon-beta; Interferons; Janus kinase; Kinetics; Knowledge; Laboratories; Lead; Left; Life; Mediating; Medical; Methods; Modeling; Modification; Molecular; Mus; Myelogenous; Operative Surgical Procedures; Pathologic; Pathology; Pharmacology; Phenotype; Play; Prevention; Preventive; Production; Proteins; Regulation; Resolution; Role; Rupture; Ruptured Abdominal Aortic Aneurysm; STAT protein; Secondary to; Signal Pathway; Small Interfering RNA; Specimen; Testing; Therapeutic; Therapeutic Agents; Tissues; Translating; Treatment Efficacy; Vascular Diseases; Vascular remodeling; Work; epigenetic regulation; experimental study; histone demethylase; histone modification; human RNA sequencing; improved; inhibitor; innovation; insight; kinase inhibitor; macrophage; monocyte; mortality; mouse model; novel; novel therapeutics; peripheral blood; pre-clinical; prevent; promoter; repaired; single-cell RNA sequencing; targeted treatment; translational approach

PROJECT SUMMARY/ABSTRACT Abdominal aortic aneurysms (AAA) are a potentially lethal vascular disease that if left untreated, can progress to aortic rupture which has a mortality rate over 80%. Equally alarming, there are currently no medical therapies available to limit AAA growth, due in large part to a lack of understanding of the molecular mechanisms underlying AAA development. Thus, a critical need exists to understand the mechanisms that govern AAA expansion. One key hallmark of AAAs is inflammatory macrophage (Mφ) infiltration into the vascular wall. We present data using human single cell RNA sequencing and murine AAA models, that the histone demethylase, JMJD3, is increased in aortic aneurysm tissue Mφs resulting in a persistent inflammatory Mφ phenotype with increased production of NFκB inflammatory mediators. Further, using human cells and our experimental murine model of AAAs, we have identified that interferon-beta (IFNβ), via a janus kinase (JAK) / signal transducer and activator of transcription (STAT) mechanism induces JMJD3 in Mφs. These results have led to our hypothesis that IFN?/JAK/STAT signaling directly increases Jmjd3 expression in aortic tissue Mφs and JMDJ3-mediated epigenetic modifications drive NFkB-mediated inflammatory genes that maintain an aortic Mφ inflammatory phenotype, thereby promoting AAA development. We further postulate that Mφ function may be restored via monocyte-Mφ-targeted inhibition of the JMJD3-mediated epigenetic modifications resulting in the resolution of inflammation and AAA stabilization. This hypothesis will be investigated via the following specific aims: Aim 1: Elucidate the regulation of NFκB-mediated inflammatory gene expression by JMJD3 in human and murine AAA monocyte/Mφs. Aim 2: Determine the IFN?/JAK/STAT-mediated mechanism(s) that regulate Mφ-specific Jmjd3 expression in human and murine AAAs. Aim 3: Examine the therapeutic efficacy of Mφ-targeted JMJD3 inhibition on AAA expansion. In this translational approach, our data will pave the way for the development of promising preventive therapeutic agents aimed at cell-specific targeting of epigenetic enzymes that mediate Mφ inflammation and thereby prevent AAA expansion and rupture.

项目摘要/摘要 腹主动脉瘤（AAA）是一种潜在的致命血管疾病，如果未治疗，可以进展 主动脉破裂，死亡率超过80％。同样令人震惊，目前没有医疗 可用于限制AAA生长的疗法，这在很大程度上是由于对分子缺乏了解 AAA开发的基础机制。这是存在一个批判性的需求，以了解 管理AAA扩展。 AAA的一个关键标志是炎症巨噬细胞（Mφ）渗入 血管壁。我们使用人类单细胞RNA测序和鼠AAA模型介绍数据， 组蛋白脱甲基酶JMJD3在主动脉动脉瘤组织Mφ中增加，导致持续性炎症 Mφ表型，NFκB炎症介质的产生增加。此外，使用人类细胞和我们 AAAS的实验鼠模型，我们通过Janus激酶（JAK） / 信号换能器和转录激活因子（STAT）机制在MφS中诱导JMJD3。这些结果有 导致我们的假设是IFN？/jak/stat信号直接增加了主动脉组织中的JMJD3表达 和JMDJ3介导的表观遗传修饰驱动NFKB介导的炎症基因，以维持 主动脉Mφ炎症表型，从而促进AAA发育。我们进一步假设Mφ 可以通过对JMJD3介导的表观遗传修饰的单核细胞Mφ靶向抑制来恢复功能 导致感染和AAA稳定的分辨率。该假设将通过 以下具体目的：目标1：通过 人和鼠AAA单核细胞/mφs中的JMJD3。目标2：确定IFN？/jak/stat介导的 调节人和鼠AAA中Mφ特异性JMJD3表达的机制。目标3：检查 对AAA扩展的Mφ靶向JMJD3的治疗效率。在这种翻译方法中，我们的 数据将为开发针对细胞特异性的承诺的预防治疗剂铺平道路 靶向介导Mφ注入并防止AAA扩展的表观遗传酶 破裂。