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:
- 金额:$ 37.43万
- 依托单位:
- 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:
- 关键词:Abdominal Aortic AneurysmAccountingActin-Binding ProteinActinsAneurysmAortic AneurysmAutomobile DrivingBiochemical GeneticsBioinformaticsBlood VesselsCessation of lifeChemicalsClinicalComplexContractile ProteinsCytoskeletonDefectDeveloped CountriesDevelopmentDissectionDown-RegulationEtiologyExtracellular Matrix ProteinsFBN1FDA approvedFunctional disorderGenesGenetic studyGoalsHealthHereditary DiseaseHistopathologyHumanIn VitroInflammationInfusion proceduresInjuryInterventionLaboratoriesLightLosartanMYH11 geneMarfan SyndromeMediatingMissionModelingMolecularMusMutationMyosin ATPaseNADPH OxidaseNF-kappa BOperative Surgical ProceduresOxidative StressPathogenesisPathway interactionsPatientsPharmaceutical PreparationsPharmacologic SubstancePlayProteinsPublic HealthPublishingRegulationResearchRoleRuptureRuptured AneurysmSeriesSignal PathwaySignal TransductionSmooth Muscle MyocytesTestingThoracic Aortic AneurysmTissuesUnited States National Institutes of HealthValidationVascular Diseasesdrug discoveryeffective therapygain of functionimprovedin vivoinsightloss of functionmouse modeloverexpressionpreventvascular 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):在工业化国家,主动脉瘤占所有死亡的1-2%。马凡氏综合征(MSF)是一种常见的遗传性疾病,代表了最充分的研究情况,了解主动脉瘤的发病机制。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。更好地了解主动脉瘤的发病机制将为开发动脉瘤的治疗方法提供新的目标。马凡氏综合征是由FBN 1蛋白突变引起的,FBN 1蛋白突变激活TGF β信号以驱动动脉瘤形成。使用携带在Marfan患者中发现的FBN 1C 1039 G突变的Marfan小鼠模型,发现氯沙坦可以预防动脉瘤形成。与成熟的TGF <$信号传导模式不同,最近发现胸主动脉瘤和夹层患者的平滑肌细胞(SMC)肌动蛋白细胞骨架蛋白(如SM <$actin(ACTA 2)和<$-肌球蛋白(MYH 11))突变,突出了动脉瘤发病机制中肌动蛋白细胞骨架收缩功能障碍的新机制。SM 22是一种肌动蛋白结合蛋白,已知在马凡氏患者的动脉瘤中显著下调。我们已发表的研究表明,SM 22缺陷破坏肌动蛋白细胞骨架,促进血管损伤后的氧化应激和血管炎症。近年来,一系列研究表明,SM 22是一种多功能蛋白,通过激活Erk 1/2和氧化应激介导的NF-κ B途径调控VSMC表型。在这里,我们建议探讨SM 22在动脉瘤发病机制中的作用。我们的初步结果表明,Sm 22在Fbn 1C 1039 G/+马凡小鼠背景中的缺失加剧了动脉瘤的形成和破裂。本提案的目的是确定SM 22在新的Marfan小鼠模型中动脉瘤形成的发病机制中的分子机制。我们推测,SM 22缺陷和FBN 1缺陷通过刺激已建立的TGF?Erk 1/2信号通路和肌动蛋白细胞骨架收缩功能障碍诱导的氧化应激和炎症信号通路的串扰来加速动脉瘤的形成和破裂。目标1:我们将在我们的Sm 22-/-Fbn 1C 1039 G/+小鼠体内系统地表征动脉瘤形成和破裂的发病机制;目的2:我们将使用成熟的分子、细胞和生物信息学方法确定SM 22缺陷对FBN 1缺陷VSMCs中TGF <$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阐明动脉瘤形成和破裂的发病机制。SM 22可能代表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,该模型密切模拟人类动脉瘤的形成和破裂。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
LI LI其他文献
Multi-Source Information Fusion for Open Innovation Decision Support System
开放式创新决策支持系统的多源信息融合
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
LI LI;SUN LU;WANG JIAYANG - 通讯作者:
WANG JIAYANG
LI LI的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('LI LI', 18)}}的其他基金
The regulatory roles of nuclear SM22 in smooth muscle phenotypic modulation
核SM22在平滑肌表型调节中的调节作用
- 批准号:
10197209 - 财政年份:2018
- 资助金额:
$ 37.43万 - 项目类别:
The regulatory roles of nuclear SM22 in smooth muscle phenotypic modulation
核SM22在平滑肌表型调节中的调节作用
- 批准号:
9978091 - 财政年份:2018
- 资助金额:
$ 37.43万 - 项目类别:
The regulatory roles of nuclear SM22 in smooth muscle phenotypic modulation
核SM22在平滑肌表型调节中的调节作用
- 批准号:
9766379 - 财政年份:2018
- 资助金额:
$ 37.43万 - 项目类别:
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 - 财政年份:2014
- 资助金额:
$ 37.43万 - 项目类别:
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 - 财政年份:2014
- 资助金额:
$ 37.43万 - 项目类别:
Chromatin Remodeling in Smooth Muscle Myogenesis and Vascular Injury Responses
平滑肌肌生成和血管损伤反应中的染色质重塑
- 批准号:
7463613 - 财政年份:2007
- 资助金额:
$ 37.43万 - 项目类别:
相似海外基金
Unraveling the Dynamics of International Accounting: Exploring the Impact of IFRS Adoption on Firms' Financial Reporting and Business Strategies
揭示国际会计的动态:探索采用 IFRS 对公司财务报告和业务战略的影响
- 批准号:
24K16488 - 财政年份:2024
- 资助金额:
$ 37.43万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Mighty Accounting - Accountancy Automation for 1-person limited companies.
Mighty Accounting - 1 人有限公司的会计自动化。
- 批准号:
10100360 - 财政年份:2024
- 资助金额:
$ 37.43万 - 项目类别:
Collaborative R&D
Accounting for the Fall of Silver? Western exchange banking practice, 1870-1910
白银下跌的原因是什么?
- 批准号:
24K04974 - 财政年份:2024
- 资助金额:
$ 37.43万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A New Direction in Accounting Education for IT Human Resources
IT人力资源会计教育的新方向
- 批准号:
23K01686 - 财政年份:2023
- 资助金额:
$ 37.43万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
An empirical and theoretical study of the double-accounting system in 19th-century American and British public utility companies
19世纪美国和英国公用事业公司双重会计制度的实证和理论研究
- 批准号:
23K01692 - 财政年份:2023
- 资助金额:
$ 37.43万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
An Empirical Analysis of the Value Effect: An Accounting Viewpoint
价值效应的实证分析:会计观点
- 批准号:
23K01695 - 财政年份:2023
- 资助金额:
$ 37.43万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Accounting model for improving performance on the health and productivity management
提高健康和生产力管理绩效的会计模型
- 批准号:
23K01713 - 财政年份:2023
- 资助金额:
$ 37.43万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
CPS: Medium: Making Every Drop Count: Accounting for Spatiotemporal Variability of Water Needs for Proactive Scheduling of Variable Rate Irrigation Systems
CPS:中:让每一滴水都发挥作用:考虑用水需求的时空变化,主动调度可变速率灌溉系统
- 批准号:
2312319 - 财政年份:2023
- 资助金额:
$ 37.43万 - 项目类别:
Standard Grant
New Role of Not-for-Profit Entities and Their Accounting Standards to Be Unified
非营利实体的新角色及其会计准则将统一
- 批准号:
23K01715 - 财政年份:2023
- 资助金额:
$ 37.43万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Improving Age- and Cause-Specific Under-Five Mortality Rates (ACSU5MR) by Systematically Accounting Measurement Errors to Inform Child Survival Decision Making in Low Income Countries
通过系统地核算测量误差来改善特定年龄和特定原因的五岁以下死亡率 (ACSU5MR),为低收入国家的儿童生存决策提供信息
- 批准号:
10585388 - 财政年份:2023
- 资助金额:
$ 37.43万 - 项目类别: