Inflammatory Pathways in Aortic Aneurysms

主动脉瘤的炎症通路

基本信息

批准号：
9468404
负责人：
KENNETH WALSH
金额：
$ 0.95万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2018-04-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9468404
关键词：
Abdominal Aortic Aneurysm Ablation Acute Adipose tissue Affect Age Aging Aneurysm Angiotensins Anti-inflammatory Antibodies Aortic Aneurysm Aortic Rupture Apolipoprotein E Attenuated Biochemical Blood Vessels Body Weight decreased Caliber Cardiovascular Diseases Cause of Death Cell Culture Techniques Cessation of life Chimeric Proteins Chronic Clinical Clinical Trials Data Development Diagnosis Disease Down-Regulation Endocrine Event Extracellular Matrix Degradation Extracellular Space Family Family suidae Fatty acid glycerol esters Fc Immunoglobulins Genetic Growth Health Histologic Human Inflammation Inflammatory Inflammatory Response Infusion procedures Knockout Mice Knowledge Lead Lesion Life Mediating Metabolic Modeling Molecular Mouse Strains Mus Myelogenous Nature Obesity Older Population Operative Surgical Procedures Pancreatic Elastase Pathology Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacology Phenotype Play Procedures Proteins Publishing Regulation Reporting Role Rupture Signal Transduction Signaling Molecule Specimen Stimulus System TNP470 Tamoxifen Testing Therapeutic Transforming Growth Factor beta Ultrasonography Vascular remodeling Video Microscopy WNT Signaling Pathway WNT5A protein abdominal aorta adipokines antitumor drug base cell type extracellular in vivo inhibitor/antagonist insight male member men mortality mouse model novel overexpression prevent public health relevance receptor repaired subcutaneous vascular inflammation

项目摘要

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

描述（由申请人提供）： AAA 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 是少数心血管疾病之一。唯一可用的治疗方法是主动脉壁手术修复，这是一种昂贵且危险的手术，对于小 AAA 患者来说不是一个有效的选择。缺乏预防或减缓 AAA 生长的药物代表了一个重要的未满足的临床需求，这凸显了对这种血管疾病的分子机制的精确了解的需要。人们普遍认为 AAA 发展的主要事件涉及炎症和蛋白水解。我们最近报道了一种新的信号轴的存在，该信号轴涉及非经典的 Wnt 信号调节剂并控制脂肪组织微环境中的炎症反应。一种新的抗炎脂肪因子，可拮抗 Wnt5a 的促炎活性，Wnt5a 是非经典 Wnt 信号传导的调节剂。我们最近发表的研究结合了人类脂肪样本的分析和遗传新型小鼠模型的表征，表明 Sfrp5。 /Wnt5a 信号传导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经典 Wnt 信号传导轴对炎症的直接贡献。与肥胖无关的条件仍有待证明。在这方面，Sfrp5 和 Wnt5a 的表达模式表明这些分子在一般血管炎症性疾病中发挥重要作用，特别是 AAA 在脂肪组织中高表达，但被严重下调。衰老（以及肥胖）时，Wnt5a 在腹主动脉中表达水平较高，并且在人类和小鼠 AAA 中表达显着上调。 Sfrp5/Wnt5a 轴的异常调节代表了对主动脉壁的一种先前未被识别的损伤，这种损伤会导致血管炎症和 AAA 的发展。此外，鉴于迫切需要防止 AAA 生长和破裂的药物，我们还旨在评估 Wnt5a 是否具有抑制作用。该项目的具体目标是： 1. 研究 Sfrp5/Wnt5a 的作用。实验性腹主动脉瘤形成中的调节轴 2. 研究 Wnt5a 辅助受体 Ror1 和 Ror2 在实验性腹主动脉瘤形成中的作用 3. 评估 Wnt5a 抑制策略在实验性腹主动脉瘤中的治疗潜力。动脉瘤