过敏介导的高IgE促进肥大细胞和血管平滑肌功能紊乱导致腹主动脉瘤形成的病理机制

Aneurysmal degeneration of the abdominal aortic and iliac arteries (referred to as abdominal aortic aneurysm, or AAA) is a common age-related and lethal disease. In China, AAA patients are remarkably increased due to the high occurence of atheroslcerosis in aging popoluations these years. To identify novel risk factors and effective nonsurgical therapies will be greatly beneficial to AAA patients for preventing the disease progression in an very early stage. Previous studies demonstrated a critical role of IgE in AAA formation, and asthma aggravates AAA formation. Therefore, we hypothesize that asthma may be a novel risk factor of AAA, which contributes to aneurysm formation and disease progression. To prove this hypothesis, the following three specific aims are proposed: ①To indentify the molecular mechanisms by which asthma-induced high IgE levels in plasma stimulates mast cells activation and secretion of tryptase, chymase and pro-inflammatory cytokine IL6, subsequently resulting in the extracellular matrix degradation and smooth muscle cell FceR1 expression and apoptosis, consequently leading to the AAA formation. ② To indentify the role of IgE-FceR1 signaling in smooth muscle cell dysfunction including MMP expression and activation, SMC phenotype switch,SMC senesence.③To determine the association between asthma and AAA delovelopment in China using clinical big data analysis and indentify the potential specific allergen. Taken together, this study will provide a rational for the assciation between allgern-specific asthma and AAA formation, and provide a novel therapeutic strategy for AAA prevention.

我国腹主动脉瘤(AAA)的发病率逐年上升，临床除手术外尚无有效治疗方法。寻找AAA的危险因素，阐明其发病机制，有利于该病的防诊治。前期数据证明高IgE与AAA形成相关，过敏性哮喘促进AAA形成，因此推断过敏可能成为AAA的全新危险因素；深入阐明其病理机制，可能为AAA的诊疗提供新靶点。本课题拟包括以下三方面研究内容：①解析过敏产生的高IgE通过激活肥大细胞分泌蛋白酶和炎性细胞因子，调节细胞外基质降解、诱导血管平滑肌细胞IgE受体FceR1的表达和凋亡，促进AAA形成的分子机制；②探索IgE介导的平滑肌细胞的功能紊乱（MMP表达、表型转换、衰老等）参与过敏导致的AAA形成的分子机制；③应用临床样本统计数据，探索我国过敏与AAA发生发展的相关性，并初步探索其可能的过敏原。本研究将从新角度进一步解析AAA的病理机制，为特异性过敏原介导的过敏成为AAA的危险因素提供理论依据，为防治AAA提供新思路

我国腹主动脉瘤(AAA)的发病率逐年上升，临床除手术外尚无有效治疗方法。寻找AAA的危险因素，阐明其发病机制，有利于该病的防诊治。前期数据提示高IgE与AAA形成具有一定的相关性，过敏性哮喘能够促进AAA形成，因此推断过敏可能成为AAA的全新危险因素。本项目期望深入阐述过敏产生的高IgE参与腹主动脉瘤发生发展的病理机制，为AAA的诊断治疗和新药开发寻找新的靶点。本项目主要以肥大细胞和血管平滑肌细胞为研究对象，探究了高IgE导致此两类功能细胞的功能紊乱促进腹主动脉瘤发生发展的病理机制，同时利用单细胞测序初步探索了腹主动脉瘤中高IgE的主要来源及相关免疫细胞的互作关系。本项目发现：1. 哮喘诱导小鼠IgE升高并加重了小鼠腹主动脉瘤形成，敲除IgE受体FcɛRI能够明显减轻由哮喘加重诱导的小鼠腹主动脉瘤的形成，并可以明显缓解AAA组织衰老及p21表达。证明哮喘诱导的高IgE能够通过lincRNAp21-p21通路促进血管平滑肌细胞衰老，从而加重AAA形成，为哮喘加重AAA的诊断和潜在治疗靶点提供了新的实验依据。2. 高IgE同时能够诱导Mep1A在腹主动脉瘤组织中的肥大细胞高表达，Mep1A促进肥大细胞分泌TNF-α，TNF-α促进平滑肌细胞分泌MMP2及细胞凋亡，敲除Mep1A可以显著缓解腹主动脉瘤的形成。提示Mep1A可能为腹主动脉瘤的潜在治疗靶点。3. 通过单细胞测序发现腹主动脉瘤中的高IgE可能来自于B细胞的局部浸润增加，以及B-T细胞之间的相互作用。本研究从新的角度进一步解析AAA的病理机制，为特异性过敏原介导的过敏成为AAA的危险因素提供理论依据，发现了导致肥大细胞和平滑肌细胞功能的紊乱的关键因子，提示lincRNAp21和Mep1A可能为AAA治疗的潜在靶点，为防治AAA和新药开发提供了新的研究方向和理论指导。