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: 9249669
• 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 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249669
• 关键词: Abdominal Aortic Aneurysm; 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; Genetic study; Goals; Hereditary Disease; Histopathology; Human; In Vitro; Inflammation; Infusion procedures; Injury; Intervention; Laboratories; Light; Losartan; MYH11 gene; Marfan Syndrome; Mediating; Mission; Modeling; Molecular; Mus; Muscle Cells; Mutation; Myosin ATPase; NADPH Oxidase; NF-kappa B; Operative Surgical Procedures; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; 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; Vascular Smooth Muscle; drug discovery; effective therapy; gain of function; improved; in vivo; insight; loss of function; mouse model; new therapeutic target; 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(申请人提供)：在工业化国家，主动脉瘤占所有死亡人数的1-2%。马凡综合征(MSF)是一种常见的遗传性疾病，是目前对主动脉瘤发病机制研究最多的一种疾病。目前，还没有被证实的预防动脉瘤进展、夹层和破裂的药物。因此，迫切需要开发有效的治疗方法。更好地了解主动脉瘤的发病机制将为发展主动脉瘤的治疗方法提供新的靶点。马凡综合征是由FBN1蛋白突变引起的，这种突变激活了转化生长因子�信号，从而推动了动脉瘤的形成。利用在马凡患者中发现的FBN1C1039G突变的马凡小鼠模型，发现氯沙坦可以预防动脉瘤的形成。与成熟的转化生长因子�信号模式不同，最近在胸主动脉瘤和夹层患者中发现的平滑肌细胞肌动蛋白细胞骨架蛋白突变，如SM�肌动蛋白(ACTA2)和�肌球蛋白(MYH11)，突显了肌动蛋白细胞骨架收缩功能障碍在动脉瘤发病中的新机制。SM22是一种肌动蛋白结合蛋白，已知在马凡患者的动脉瘤中显著下调。我们已发表的研究表明，SM22缺乏扰乱肌动蛋白细胞骨架，并促进氧化应激和血管损伤的血管炎症。最近的一系列研究表明，SM22是一种多功能蛋白，它通过激活ERK1/2和氧化应激介导的NF-kB通路来调节VSMC的表型调节。在此，我们建议探讨SM22在动脉瘤发病机制中的作用。我们的初步结果表明，Fbn1C1039G/+Marfan小鼠背景中Sm22的缺失会加剧动脉瘤的形成和破裂。本研究的目的是在一种新的Marfan小鼠模型中确定SM22在动脉瘤形成机制中的分子机制。我们假设SM22缺陷与FBN1缺陷通过刺激已建立的转化生长因子�ERK1/2信号通路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的串扰而加剧动脉瘤的形成和破裂。目的1：我们将在体内系统地研究SM22-/-Fbn1C1039G/+小鼠动脉瘤的形成和破裂的发病机制；目的2：利用成熟的分子、细胞和生物信息学手段，研究SM22缺乏转化生长因子�ERK1/2、氧化应激和NF-kB通路激活的分子机制。这项研究的成功完成将有助于揭示动脉瘤形成和破裂的机制。SM22可能是主动脉瘤新疗法的靶点。重要的是，这项研究将为一种新的小鼠动脉瘤模型提供验证，该模型非常接近人类动脉瘤的形成和破裂。