Inflammatory Pathways in Aortic Aneurysms

 描述(申请人提供)：AAAS是与年龄相关的腹主动脉局部扩张，多年来不断扩张，经常导致主动脉破裂，死亡率高达90%。重要的是，AAA是为数不多的没有药物治疗的心血管疾病之一。唯一可用的治疗方法是手术修复主动脉壁，这是一种昂贵且危险的手术，对于患有小型AAA的患者来说不是一个有效的选择。因此，缺乏预防或减缓AAA增长的药物是一个重要的未得到满足的临床需求，这突显了对这种血管疾病背后的分子机制的精确了解的必要性。人们普遍认为，AAA发生的主要事件涉及血管壁上细胞外基质的炎症和蛋白降解。我们最近报道了一个新的信号轴的存在，它涉及非规范的Wnt信号调节器，并控制脂肪组织微环境中的炎症反应。具体地说，我们确定Sfrp5是一种新的抗炎脂肪因子，它拮抗Wnt5a的促炎活性，Wnt5a是非典范Wnt信号的调节因子。我们最近发表的研究结合了对人类脂肪样本的分析和对新的小鼠遗传模型的表征，表明Sfrp5/Wnt5a信号是脂肪组织炎症和全身代谢健康的调节因子。然而，Sfrp5的内分泌作用以及这种非规范的Wnt信号轴对炎症条件的直接贡献与肥胖无关仍有待证实。在这方面，Sfrp5和Wnt5a的表达模式表明这些分子在血管炎症障碍，特别是AAA中发挥着重要作用。Sfrp5在脂肪组织中高度表达，但随着年龄的增长(以及肥胖)而显著下调。相反，Wnt5a在腹主动脉中高水平表达，在人和小鼠AAA中显著上调。基于这些发现，我们建议检验这样一种假设，即Sfrp5/Wnt5a轴的异常调节代表了一种以前未被认识到的对主动脉壁的侮辱，从而促进了血管炎症和AAA的发展。此外，鉴于迫切需要预防AAA生长和破裂的药物，我们还旨在评估Wnt5a抑制策略在预防预先建立的实验性AAA生长方面是否有效。本项目的具体目的是：1.探讨Sfrp5/Wnt5a调节轴在实验性腹主动脉瘤形成中的作用。2.探讨WNT5a辅受体Ror1和Ror2在实验性腹主动脉瘤形成中的作用。3.评价Wnt5a抑制策略在实验性腹主动脉瘤中的治疗潜力

 DESCRIPTION (provided by applicant): AAAs are age-associated localized dilations of the abdominal aorta that expand over the years and frequently lead to aortic rupture with a mortality rate as high as 90 %. Importantly, AAAs are one of the few cardiovascular disorders for which there is no pharmacological therapy. The only available treatment is surgical repair of the aortic wall, an expensive and risky procedure that is not a valid option for patients with small AAAs. Thus, the lack of a drug that prevents or slows down AAA growth represents an important unmet clinical need, which highlights the need for a precise knowledge of the molecular mechanisms underlying this vascular condition. It is widely accepted that the primary events in AAA development involve inflammation and proteolytic degradation of extracellular matrix in the vessel wall. We recently reported the existence of a new signaling axis that involves non-canonical Wnt signaling modulators and controls the inflammatory response in the adipose tissue micro-environment. Specifically, we identified Sfrp5 as a new anti-inflammatory adipokine, which antagonizes the pro-inflammatory activity of Wnt5a, a regulator of non-canonical Wnt signaling. Our recently published studies have combined the analysis of human fat specimens and the characterization of novel genetic mouse models to show that Sfrp5/Wnt5a signaling is a regulator of adipose tissue inflammation and systemic metabolic health. However, the endocrine actions of Sfrp5 and the direct contribution of this non- canonical Wnt signaling axis to inflammatory conditions independent of obesity remain to be demonstrated. In this regard, the expression patterns of Sfrp5 and Wnt5a suggest an important role of these molecules in vascular inflammatory disorders in general and AAAs in particular. Sfrp5 is highly expressed in adipose tissue, but severely downregulated by aging (as well as obesity). Conversely, Wnt5a is expressed at high levels in the abdominal aorta and markedly upregulated in human and mouse AAAs. Based on these findings, we propose to test the hypothesis that the aberrant regulation of the Sfrp5/Wnt5a axis represents a previously unrecognized insult to the aortic wall that contributes to vascular inflammation and AAA development. Additionally, given the urgent need for drugs that prevent AAA growth and rupture, we also aim to evaluate whether Wnt5a-inhibitory strategies are effective at preventing the growth of pre-established experimental AAAs. The specific aims of this project are: 1. To investigate the role of the Sfrp5/Wnt5a regulatory axis in experimental abdominal aortic aneurysm formation. 2. To investigate the role of the Wnt5a co-receptors Ror1 and Ror2 in experimental abdominal aortic aneurysm formation. 3. To evaluate the therapeutic potential of Wnt5a-inhibitory strategies in the setting of experimental abdominal aortic aneurysms