JMJD3 Regulates Abdominal Aortic Aneurysm Expansion

项目总结/摘要 腹主动脉瘤（AAA）是一种潜在的致命性血管疾病，如果不及时治疗，可能会进展 主动脉破裂死亡率超过80%同样令人震惊的是，目前没有医疗 限制AAA生长的治疗方法，很大程度上是由于缺乏对AAA分子机制的了解。 AAA发展的基础机制。因此，迫切需要了解 管理AAA扩展。AAAs的一个关键标志是炎性巨噬细胞（M φ）浸润到 血管壁我们使用人类单细胞RNA测序和小鼠AAA模型提供数据， 组蛋白去甲基化酶JMJD 3在主动脉瘤组织M φ中增加，导致持续性炎性反应。 M φ表型与NF κ B炎症介质的产生增加。此外，使用人类细胞和我们的 在AAAs的实验小鼠模型中，我们已经确定干扰素β（IFN β）通过Janus激酶（JAK）/ 信号转导子和转录激活子（STAT）机制在M φ中诱导JMJD 3。这些结果 导致我们的假设，干扰素？/ JAK/STAT信号直接增加主动脉组织M φ中Jmjd3的表达 JMDJ3介导的表观遗传修饰驱动NF κ B介导的炎症基因， 主动脉M φ炎性表型，从而促进AAA的发展。我们进一步假设M φ 通过单核细胞-M φ靶向抑制JMJD3介导的表观遗传修饰， 导致炎症消退和AAA稳定。这一假设将通过 目的1：阐明NF κ B介导的炎症基因表达的调控， 人和鼠AAA单核细胞/M φ中的JMJD3。目的2：测定IFN？/ JAK/STAT介导 调节人和鼠AAA中M φ特异性Jmjd3表达的机制。目标3：检查 M φ靶向的JMJD3抑制对AAA扩张的治疗功效。在这种翻译方法中，我们 这些数据将为开发针对细胞特异性的有前途的预防性治疗剂铺平道路。 靶向介导M φ炎症的表观遗传酶，从而防止AAA扩张， 破裂

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.