免疫球蛋白E及其受体在腹动脉瘤发病过程中的作用

Aneurysmal degeneration of the abdominal aortic and iliac arteries (referred to as abdominal aortic aneurysm, or AAA) is a common age-related disease. Atherosolcerosis has been recognized as one of the most important AAA risk factors.　It will be very beneficial for AAA patients to identify specific diagnostic biomarkers and effective nonsurgical therapies to halt disease progression at early stage. Our previous studies have demonstrated a direct link of IgE with atherogenesis.Therefore we hypothesize that IgE-FceR1 may contribute to the formation and progression of AAA. Three of the following aims are proposed to verify this hypothesis: ① To determine the association between plasma IgE and AAA delovelopment using classical AngII-induced AAA animal model. ②To examine the roles of deficiency or pharmacological interruption of IgE-FceR1 interaction in AAA formation. ③To explore the molecular mechanisms by which IgE stimulates macrophage MMPs activation and pro-inflammatory cytokine IL6 expression; resulting in the extracellular matrix degradation, smooth muscle cell apoptosis, and subsequently AAA formation. Taking together, this study will bring about a paradigm shift in our understanding of IgE functions in diseases other than hypersensitivity. The potential implication of IgE in atherosolcerosis and subsequent AAA formation may suggest that IgE is a novel biomarker of AAA at early stage. Further mechanistic study in this proposal will greatly facilitate the identifaction of therapeutic targets for AAA and the development of effective early intervention for patients with AAA.

腹主动脉瘤是腹主动脉壁退化变薄进而膨胀，最终破裂出血致患者死亡的高危疾病。因其发病机制仍不完全清楚，临床上缺乏有效的诊断标记物和治疗药物。我们前期的工作证明IgE与动脉粥样硬化密切相关，而动脉粥样硬化是腹主动脉瘤的主要诱因之一。因此推断IgE-FceR1可能促进腹主动脉瘤的形成。本课题拟从以下三方面验证此假设：①建立腹主动脉瘤动物模型，确立血浆IgE含量与腹主动脉瘤发生发展的相关性；②使用FceR1敲除小鼠和IgE/FceR1抗体，检测阻断IgE-FceR1信号减缓腹主动脉瘤的可能性；③阐明IgE-FceR1通过刺激巨噬细胞介导的MMPs和IL6的表达，导致细胞外基质的降解以及血管平滑肌细胞凋亡，从而促进腹主动脉瘤形成的分子病理学机制。本课题将突破传统的IgE诱导超敏反应的功能研究，赋予IgE及其受体在疾病机制研究中新的角色，为IgE成为腹主动脉瘤新的血浆诊断标记物和治疗靶点提供科学依据。

免疫球蛋白E（IgE）通过结合肥大细胞和嗜碱性粒细胞来激活免疫。众所周知，IgE及其受体FceR1在过敏性哮喘气道炎症的发生和重塑中起着关键作用。最近的研究表明，IgE在腹主动脉瘤（AAA）的发病机制中也起着重要作用。然而，IgE促进AAA的机制仍然不清楚。我们发现OVA诱导的哮喘小鼠模型中，引发血清中高水平的IgE加重了AAA，但在FceR1-/-小鼠中，IgE不在能够加重AAA的发生发展。同时，体外研究表明，IgE通过上调lincRNA-p21促进p21的表达而不改变p53的表达，诱导血管平滑肌细胞衰老。通过这一机制，IgE加重了ApoE-/-小鼠的AAA，而在体外和体内都证明可以被lincRNA-p21的沉默所阻断。本研究提示，IgE激活了lincRNA p21-p21通路，诱导SMC衰老，进而促进AAA的形成；换言之，lincRNA-p21是治疗哮喘加重的AAA的潜在靶点。