Dedicator of cytokinesis 2 in abdominal aortic aneurysm

腹主动脉瘤胞质分裂2的奉献者

基本信息

批准号：
10417112
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10417112
关键词：
Abdominal Aortic Aneurysm Affect Aneurysm Aortic Aneurysm Apolipoprotein E Arterial Medias Arteries Attenuated Basic Science Blood Vessels Bone Marrow Transplantation CCL2 gene Cell physiology Cells Collagen Contractile Proteins Core Facility Cytokinesis Data Development Disease Elastases Elastin Environment Equipment Extracellular Matrix Extracellular Matrix Degradation Extracellular Matrix Proteins Gelatinase A Goals Hematopoietic Histologic Homeostasis Human Immune Infiltration Inflammation Inflammatory Infusion procedures Interleukin-1 beta Intracranial Aneurysm JUN gene Knockout Mice Knowledge Laboratories Lead Light Medial Mediating Modeling Molecular Mus NF-kappa B Outcome Patients Peptide Hydrolases Pharmacological Treatment Pharmacology Phenotype Play Positioning Attribute Prevention strategy Prevention therapy Production Research Resources Role Smooth Muscle Myocytes T-Lymphocyte TNF gene Techniques Testing Tissues Tunica Media United States National Library of Medicine Universities Vascular Smooth Muscle Vascular remodeling animal facility clinical application genetic approach improved in vivo injured loss of function macrophage mouse model novel novel strategies novel therapeutics prevent programs therapeutically effective vascular inflammation

项目摘要

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.

摘要/摘要腹主动脉瘤（AAA）是一种潜在的致命疾病，缺乏药理治疗。主动脉墙炎症和随后的细胞外基质（ECM）蛋白的降解，尤其是弹性蛋白破裂，是AAA开发的决定因素。血管炎症，尤其是巨噬细胞浸润和炎症SMC表型会导致破坏ECM的蛋白水解酶的产生稳态导致船只较弱的容器壁，从而导致AAA形成。但是，有关键关于控制血管炎症和关键因素的知识差距 ECM失调。我们令人兴奋炎症SMC表型和AAA形成的核心作用。 DOCK2缺陷（DOCK2 - / - ）在小鼠中，小鼠显着减弱了AAA的形成（弹性蛋白破裂减少并改善了动脉壁完整性）并减少炎症SMC表型的诱导。因此，dock2 - / - 抑制 SMC中的单核细胞趋化蛋白1（MCP-1）和基质金属蛋白酶-2（MMP2）的表达同时还原收缩SMC标记。一致地，动脉瘤动脉介质中的巨噬细胞浸润是在Dock2 - / - 小鼠中阻塞。此外，dock2表达与人类的动脉瘤形成有关患者。这些数据强烈支持了一个新的假设，该假设dock2诱导了炎症SMC表型导致血管炎症，弹性蛋白断裂以及AAA形成。使用主鼠标和人类SMC，体内DOCK2 SMC-，巨噬细胞和T细胞特异性基因敲除小鼠模型与分子，细胞，组织学和药理学方法，我们将1）确定机制 DOCK2调节炎症SMC表型； 2）检验Dock2促进AAA的假设通过体内刺激炎症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型机制，这是可能会促进我们对AAA形成的理解，并最终导致发展的新策略有效治疗AAA的治疗疗法。