Dedicator of cytokinesis 2 in abdominal aortic aneurysm

腹主动脉瘤胞质分裂2的奉献者

• 批准号: 10063651
• 负责人: Shiyou Chen
• 金额: $ 52.32万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063651
• 关键词: Dedicator; cytokinesis; abdominal; aortic; aneurysm

Summary/Abstract Abdominal aortic aneurysm (AAA) is a potentially lethal disease that lacks pharmacological treatment. Aortic wall inflammation and subsequent degradation of extracellular matrix (ECM) proteins, especially the elastin breakage, are the determining factors for the development of AAA. Vascular inflammation, particularly macrophage infiltration and inflammatory SMC phenotype, causes the production of proteolytic enzymes that disrupt ECM homeostasis leading to a weakened vessel wall and consequently AAA formation. However, there is a critical knowledge gap concerning the mechanism(s) or key factor(s) controlling both the vascular inflammation and the ECM dysregulation. Our exciting preliminary data indicate that dedicator of cytokinesis 2 (DOCK2) plays a central role in the induction of inflammatory SMC phenotype and AAA formation. DOCK2 deficiency (DOCK2-/-) in mice significantly attenuates AAA formation (with decreased elastin breakage and improved artery wall integrity) and diminishes the induction of inflammatory SMC phenotype. Consequently, DOCK2-/- inhibits the expression of monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-2 (MMP2) in SMCs while restoring contractile SMC markers. Consistently, the macrophage infiltration in aneurysm arterial media is blocked in DOCK2-/- mice. Moreover, DOCK2 expression is associated with aneurysm formation in human patients. These data strongly support a novel hypothesis that DOCK2 induces inflammatory SMC phenotype leading to vascular inflammation, elastin breakage, and consequently AAA formation. Using primary mouse and human SMCs, in vivo DOCK2 SMC-, macrophage-, and T cell- specific knockout mouse models combining with molecular, cellular, histological, and pharmacological approaches, we will 1) determine the mechanisms by which DOCK2 regulates inflammatory SMC phenotype; and 2) test the hypothesis that DOCK2 promotes AAA formation by stimulating inflammatory SMC phenotype in vivo. Successful completion of the proposed studies will establish novel mechanisms regulating SMC inflammatory phenotype and vascular inflammation, which are likely to advance our understanding of the AAA formation and ultimately lead to novel strategies for developing effective therapeutics to treat AAA.

总结/摘要 腹主动脉瘤（AAA）是一种缺乏药物治疗的潜在致死性疾病。主动脉壁 炎症和随后的细胞外基质（ECM）蛋白的降解，特别是弹性蛋白断裂， 是AAA发展的决定性因素。血管炎症，特别是巨噬细胞 浸润和炎性SMC表型，导致产生破坏ECM的蛋白水解酶 体内平衡导致血管壁变弱，从而形成AAA。然而，有一个关键的 关于控制血管炎症和炎症的机制或关键因素的知识差距 ECM失调。我们令人兴奋的初步数据表明，胞质分裂奉献者2（DOCK 2）在细胞分裂中起着重要作用。 在诱导炎性SMC表型和AAA形成中起中心作用。DOCK 2缺陷（DOCK 2-/-） 在小鼠中显著减弱AAA形成（具有减少的弹性蛋白断裂和改善的动脉壁 完整性）并减少炎性SMC表型的诱导。因此，DOCK 2-/-抑制了 单核细胞趋化蛋白-1和基质金属蛋白酶-2在平滑肌细胞中的表达 同时恢复收缩性SMC标记物。因此，巨噬细胞浸润动脉瘤动脉介质是 在DOCK 2-/-小鼠中阻断。此外，DOCK 2表达与人类动脉瘤形成相关， 患者这些数据有力地支持了一个新的假设，即DOCK 2诱导炎性SMC表型 导致血管炎症、弹性蛋白断裂，并因此形成AAA。使用主鼠标和 人SMC、体内DOCK 2 SMC-、巨噬细胞-和T细胞特异性敲除小鼠模型， 分子，细胞，组织学和药理学方法，我们将1）确定机制， DOCK 2调节炎性SMC表型;和2）测试DOCK 2促进AAA的假设 通过刺激体内炎性SMC表型形成。成功完成拟议的研究 将建立调节SMC炎症表型和血管炎症的新机制， 可能会促进我们对AAA形成的理解，并最终导致开发新的战略， 治疗AAA的有效疗法。