The Role of SM22 in the Pathogenesis of Aortic Aneurysms

SM22 在主动脉瘤发病机制中的作用

• 批准号: 8697911
• 负责人: LI LI
• 金额: $ 38万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-04 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697911
• 关键词: Abdominal Aortic Aneurysm; Accounting; Actin-Binding Protein; Actins; Aneurysm; Aortic Aneurysm; Automobile Driving; Biochemical Genetics; Bioinformatics; Blood Vessels; Cessation of life; Chemicals; Clinical; Complex; Contractile Proteins; Cytoskeleton; Defect; Developed Countries; Development; Dissection; Down-Regulation; Etiology; Extracellular Matrix Proteins; FBN1; FDA approved; Functional disorder; Genes; Goals; Hereditary Disease; Histopathology; Human; In Vitro; Inflammation; Infusion procedures; Injury; Intervention; Laboratories; Light; Losartan; MYH11 gene; Marfan Syndrome; Mediating; Mission; Modeling; Molecular; Mus; Mutation; Myosin ATPase; NADPH Oxidase; NF-kappa B; Operative Surgical Procedures; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Play; Proteins; Public Health; Publishing; Regulation; Research; Role; Rupture; Ruptured Aneurysm; Series; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Testing; Thoracic Aortic Aneurysm; Tissues; United States National Institutes of Health; Validation; Vascular Diseases; drug discovery; effective therapy; gain of function; improved; in vivo; insight; loss of function; mouse model; overexpression; prevent; public health relevance; vascular inflammation

DESCRIPTION (provided by applicant): Aortic aneurysms account for 1-2% of all deaths in industrialized countries. Marfan syndrome (MSF) is a common genetic disease that represents the most well studied situation for understanding the pathogenesis of aortic aneurysms. Currently, there are no proven drugs preventing aneurysm progression, dissection and rupture. Therefore, there is a pressing need to develop effective therapies. A better understanding of the pathogenesis of aortic aneurysms should provide new targets for developing treatments to aneurysms. Marfan syndrome is caused by FBN1 protein mutations that activate TGF¿ signaling to drive aneurysm formation. Using a Marfan mouse model that harbors the FBN1C1039G mutation found in Marfan patients, losartan was discovered to prevent aneurysm formation. Distinct from the well-established TGF¿ signaling paradigm, recent discoveries of mutations in smooth muscle cell (SMC) actin cytoskeleton proteins such as SM ¿actin (ACTA2) and ¿-myosin (MYH11) in patients with thoracic aortic aneurysm and dissection highlight a new mechanism of actin cytoskeleton contractile dysfunction in the pathogenesis of aneurysms. SM22, an actin binding protein, is known to significantly downregulated in the aneurysms of Marfan patients. Our published studies demonstrate that SM22 deficiency disrupts actin cytoskeleton and promotes oxidative stress and vascular inflammation upon vascular injury. Recently, a series of studies show that SM22 is a multifunctional protein that regulates VSMC phenotypic modulation via activating Erk1/2, and Oxidative stress-mediated NF-kB pathways. Here we propose to explore the role of SM22 in the pathogenesis of aneurysms. Our preliminary results show that deletion of Sm22 in the Fbn1C1039G/+ Marfan mouse background exacerbates aneurysm formation and rupture. The goal of this proposal is to determine the molecular mechanisms of SM22 in the pathogenesis of aneurysm formation in a new Marfan mouse model. We hypothesize that SM22 deficiency with defective FBN1 aggravates aneurysm formation and rupture by stimulating the crosstalk of both the established TGF¿Erk1/2 signaling pathways and the actin cytoskeleton contractile dysfunction-induced oxidative stress and inflammation signaling pathways. Aim 1: we will systematically characterize the pathogenesis of aneurysm formation and rupture in our Sm22-/-Fbn1C1039G/+ mice in vivo; Aim 2: we will determine the molecular mechanisms of SM22 deficiency on TGF¿Erk1/2, oxidative stress and NF-kB pathway activation in FBN1 defective VSMCs using well established molecular, cellular and bioinformatics approaches. Successful completion of this research will shed light on the pathogenesis of aneurysm formation and rupture. SM22 may represent a target for new therapies for aortic aneurysms. Importantly, this study will provide validation for a new mouse aneurysm model that mimics closely human aneurysm formation and rupture.

描述（由适用提供）：主动脉动脉瘤占工业化国家所有死亡人数的1-2％。 Marfan综合征（MSF）是一种常见的遗传疾病，代表了研究最良好的情况，用于理解主动脉动脉瘤的发病机理。目前，没有可靠的药物可以防止动脉瘤进展，解剖和破裂。因此，有迫切需要开发有效的疗法。更好地了解主动脉瘤的发病机理应为开发针对动脉瘤的治疗方法提供新的靶标。 Marfan综合征是由FBN1蛋白突变引起的，该突变激活TGF信号以驱动动脉瘤形成。使用Marfan小鼠模型，该模型携带了Marfan患者中发现的FBN1C1039G突变，发现了氯沙坦以防止动脉瘤形成。与建立良好的TGF信号范式不同，在平滑肌细胞（SMC）肌动蛋白细胞骨架蛋白（如Sm stecin（acta2）和麦乳蛋白（MYH11））中的最新发现，胸痛动脉症患者和disection症患者的新机械性伴随着肌动蛋白的机械性疾病的病情，动脉瘤。已知SM22是一种肌动蛋白结合蛋白，在Marfan患者的动脉瘤中显着下调。我们发表的研究表明，SM22缺陷会破坏肌动蛋白细胞骨架，并促进血管损伤后的氧化应激和血管感染。最近，一系列研究表明，SM22是一种多功能蛋白，可通过激活ERK1/2和氧化应激介导的NF-KB途径来调节VSMC表型调节。在这里，我们建议探索SM22在动脉瘤发病机理中的作用。我们的初步结果表明，在FBN1C1039G/+ Marfan小鼠背景中，SM22的删除加剧了动脉瘤形成和破裂。该建议的目的是确定新的Marfan小鼠模型中动脉瘤形成的发病机理中SM22的分子机制。我们假设SM22缺乏FBN1缺乏通过刺激已建立的TGF¿ERK1/2信号通路的串扰和肌动蛋白细胞骨架收缩功能障碍诱导的氧化应激和炎症信号通路，从而加剧了动脉瘤的形成和破裂。 AIM 1：我们将系统地表征我们SM22 - / - FBN1C1039G/+小鼠体内动脉瘤形成和破裂的发病机理； AIM 2：我们将使用良好的分子，细胞和生物信息学方法来确定TGF¿ERK1/2上SM22缺乏的分子机制，氧化应激和NF-KB途径激活。这项研究的成功完成将阐明动脉瘤形成和破裂的发病机理。 SM22可能代表了主动脉瘤新疗法的靶标。重要的是，这项研究将为新的小鼠动脉瘤模型提供验证，该模型模仿了人类动脉瘤形成和破裂。