The Role of SM22 in the Pathogenesis of Aortic Aneurysms

SM22 在主动脉瘤发病机制中的作用

基本信息

批准号：
8831725
负责人：
LI LI
金额：
$ 37.43万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8831725
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 Genetic study Goals Health 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 vascular inflammation

项目摘要

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（由申请人提供）：主动脉瘤占工业化国家所有死亡的 1-2%，马凡综合征 (MSF) 是一种常见的遗传性疾病，代表了目前对主动脉瘤发病机制研究最多的情况。目前还没有经过验证的药物可以预防动脉瘤进展、夹层和破裂，因此迫切需要开发有效的治疗方法。动脉瘤应该为开发治疗动脉瘤的新靶点，马凡综合征是由激活 TGF 的 FBN1 蛋白突变引起的。使用在马凡患者中发现的带有 FBN1C1039G 突变的马凡小鼠模型，发现氯沙坦可以预防动脉瘤形成，这与公认的 TGF 不同。信号范式，最近发现平滑肌细胞 (SMC) 肌动蛋白细胞骨架蛋白（例如 SM）突变 ¿肌动蛋白 (ACTA2) 和 ¿胸主动脉瘤和夹层患者中的肌球蛋白（MYH11）强调了动脉瘤发病机制中肌动蛋白细胞骨架收缩功能障碍的新机制，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着下调。最近，证明 SM22 缺陷会破坏肌动蛋白细胞骨架并促进血管损伤时的氧化应激和血管炎症。一系列研究表明，SM22 是一种多功能蛋白，通过激活 Erk1/2 和氧化应激介导的 NF-kB 通路来调节 VSMC 表型调节，我们的初步结果是探讨 SM22 在动脉瘤发病机制中的作用。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。我们的目标是确定 SM22 在新 Marfan 小鼠模型中动脉瘤形成发病机制中的分子机制，我们发现 SM22 缺陷和 FBN1 缺陷会通过刺激已建立的 TGF 的串扰来加剧动脉瘤形成和破裂。 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目标 1：我们将系统地表征 Sm22-/-Fbn1C1039G/+ 小鼠体内动脉瘤形成和破裂的发病机制。我们将确定 SM22 缺陷对 TGF 的分子机制¿使用成熟的分子、细胞和生物信息学方法，成功完成 FBN1 缺陷 VSMC 中的 Erk1/2、氧化应激和 NF-kB 通路激活，将揭示动脉瘤形成和破裂的发病机制，可能是 SM22 的新靶点。重要的是，这项研究将为密切模仿人类动脉瘤形成的新小鼠动脉瘤模型提供验证。和破裂。