Impact of the micromechanical environment on inflammation in AAA progression
微机械环境对 AAA 进展中炎症的影响
基本信息
- 批准号:8900331
- 负责人:
- 金额:$ 18.53万
- 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:2014-08-01 至 2017-06-30
- 项目状态:已结题
- 来源:
- 关键词:Abdominal Aortic AneurysmAffectAgingAneurysmAngiotensin IIAnimalsAnti-Inflammatory AgentsAnti-inflammatoryAortaApolipoprotein EApoptoticArteriesBehaviorBiological AssayBiomechanicsBlood VesselsBreedingCause of DeathCell Culture TechniquesCellsCollagenCollagen FiberDataDefectDepositionDevelopmentDiagnosisDiseaseDown-RegulationElastasesElastinElderlyEnvironmentExcisionExtracellular MatrixFibroblastsFlow CytometryFoundationsFunctional disorderFutureGelHealthHeatingHistologicHuman CharacteristicsIn VitroInfiltrationInflammationInflammatoryInflammatory InfiltrateInflammatory ResponseInfusion proceduresKnowledgeLipoproteinsMacrophage Colony-Stimulating FactorMechanicsMediatingModelingMouse StrainsMusMutant Strains MiceOperative Surgical ProceduresPathologic ProcessesPatientsPeptide HydrolasesPerfusionPharmacologic SubstancePlayPopulationPropertyRiskRisk FactorsRuptureRuptured AneurysmSmooth Muscle MyocytesSourceTestingTherapeuticTissuesTransgenic MiceUnited StatesVascular DiseasesWorkage relatedbasecrosslinkcytokinecytotoxicdesigndisabilitydrug developmentexpectationin vitro testingin vivoinsightmacrophagemonocytemutantnovelpreventvascular inflammation
项目摘要
DESCRIPTION (provided by applicant): Aging is the most important yet least understood risk factor for abdominal aortic aneurysm (AAA), a common, progressive vascular disease with high lethality. The vascular extracellular matrix (ECM) changes with aging, characterized by stiffer and less organized collagen fibers. We hypothesize that these age-related ECM changes predispose older arteries to aneurysm not only by altering vessel mechanical properties but also by influencing the functions of infiltrating inflammatory cells. In this R21, we propose to specifically test how age-related collagen changes affect the inflammatory response during the course of aneurysm development using the transgenic mouse strain Col1a1. The homozygous mutant animals (Col1a1R/R) have been shown to display excessive collagen accumulation and subsequent ECM stiffening as well as exacerbated aneurysm formation. Two Specific Aims are proposed. In Aim 1, we will test whether ECM stiffening accelerates AAA progression and intensifies vascular inflammation by subjecting Col1a1 mutant and wildtype (Col1a1+/+) mice to AAA induction via intraluminal perfusion with elastase (AAA) or heat-inactivated elastase (sham). This so called elastase model is widely accepted for its duplication of major pathological characteristics of human AAAs. We will focus on macrophage-mediated inflammation because macrophages are the predominant type of inflammatory cells found in aneurysmal aorta and are thought to be the major source of elastin degrading proteases. In addition to macrophage recruitment, we will examine macrophage differentiation with the expectation that ECM stiffening facilitates differentiation of the proinflammatory subtype or M1 macrophages or/and suppresses differentiation of the anti-inflammatory subtype or M2 macrophages. Currently, how macrophage subtypes are distributed in aneurysmal tissue and how subtype differentiation may be affected by aging ECM is completely unknown. In Aim 2, we propose culture monocytes (the precursors of macrophages) from wildtype or mutant mice in collagen gels of increasing stiffness to study how collagen-mediated ECM stiffening influences the recruitment and differentiation of inflammatory cells. The results obtained from this study will provide a new concept in understanding aging-associated AAA formation and lay a foundation for future mechanistic studies and drug development. Therefore, our work is significant, novel, and translational.
描述(由申请人提供):衰老是腹主动脉瘤(AAA)的最重要的最重要的危险因素,腹主动脉瘤是一种常见的,进行性的,具有高致死性的进行性血管疾病。血管外基质(ECM)随老化而变化,其特征是较硬且组织较少的胶原蛋白纤维。我们假设这些与年龄相关的ECM不仅可以通过改变血管机械性能,而且还影响浸润炎症细胞的功能,使旧动脉变化不仅是通过改变血管机械性能。在此R21中,我们建议使用转基因小鼠菌株COL1A1在动脉瘤发育过程中如何影响年龄相关的胶原蛋白变化如何影响炎症反应。纯合突变动物(COL1A1R/R)已显示出表现出过多的胶原蛋白积累,随后的ECM僵硬以及加剧的动脉瘤形成。提出了两个具体目标。在AIM 1中,我们将通过将Col1a1突变体和WildType(Col1a1+/+)小鼠(通过用弹性酶(AAA))或热激活的弹性酶(sham)对AAA诱导,测试ECM是否会加速AAA进展并加剧血管炎症。这种所谓的弹性酶模型因其重复人类AAA的重复而被广泛接受。我们将重点关注巨噬细胞介导的炎症,因为巨噬细胞是动脉瘤主动脉中发现的主要类型的炎性细胞类型,被认为是弹性蛋白降解蛋白酶的主要来源。除巨噬细胞募集外,我们还将检查巨噬细胞的分化,因为ECM僵硬的期望有助于促炎性亚型或M1巨噬细胞的分化或///或抑制抗炎亚型或M2巨噬细胞的分化。当前,巨噬细胞亚型如何分布在动脉瘤组织中,以及在ECM上衰老的亚型分化如何影响。在AIM 2中,我们提出了从野生型或突变小鼠中的培养单核细胞(巨噬细胞的前体)中的胶原蛋白凝胶,以提高刚度的较高刚度,以研究胶原蛋白介导的ECM僵化如何影响炎症细胞的募集和分化。从这项研究中获得的结果将为了解与衰老相关的AAA形成,并为未来的机械研究和药物开发奠定了基础。因此,我们的工作是重要的,新颖的和翻译的。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Naomi C Chesler其他文献
MRI assessment of aortic flow and pulse wave velocity in response to exercise
- DOI:
10.1186/1532-429x-17-s1-m2 - 发表时间:
2015-02-03 - 期刊:
- 影响因子:
- 作者:
Jacob Macdonald;Omid Forouzan;Jared Warczytowa;Oliver Wieben;Christopher J Francois;Naomi C Chesler - 通讯作者:
Naomi C Chesler
Exercise cardiac MR assessment of diastolic function
- DOI:
10.1186/1532-429x-17-s1-p26 - 发表时间:
2015-02-03 - 期刊:
- 影响因子:
- 作者:
Christopher J Francois;Omid Forouzan;Jared Warczytowa;Jacob A Macdonald;Oliver Wieben;Naomi C Chesler - 通讯作者:
Naomi C Chesler
4D flow-sensitive MR estimation of pulmonary vascular resistance
- DOI:
10.1186/1532-429x-15-s1-p128 - 发表时间:
2013-01-30 - 期刊:
- 影响因子:
- 作者:
Alejandro Roldán-Alzate;Christopher Francois;Oliver Wieben;Naomi C Chesler;Alex Frydrychowicz - 通讯作者:
Alex Frydrychowicz
Non - invasive right ventricular efficiency using 4D flow MRI
- DOI:
10.1186/1532-429x-17-s1-q58 - 发表时间:
2015-02-03 - 期刊:
- 影响因子:
- 作者:
Alejandro Roldán-Alzate;Scott W Grogan;Heidi B Kellihan;Alessandro Bellofiore;Naomi C Chesler;Oliver Wieben;Christopher J Francois - 通讯作者:
Christopher J Francois
Naomi C Chesler的其他文献
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{{ truncateString('Naomi C Chesler', 18)}}的其他基金
Mechanobiological mechanisms of pulmonary hypertension secondary to left heart failure
左心衰竭继发肺动脉高压的力学生物学机制
- 批准号:
10847887 - 财政年份:2020
- 资助金额:
$ 18.53万 - 项目类别:
Mechanobiological mechanisms of pulmonary hypertension secondary to left heart failure
左心衰竭继发肺动脉高压的力学生物学机制
- 批准号:
10414922 - 财政年份:2020
- 资助金额:
$ 18.53万 - 项目类别:
Impact of sex and sex hormones on mechanobiological mechanisms of pulmonary hypertension secondary to left heart failure
性和性激素对左心衰竭继发肺动脉高压力学生物学机制的影响
- 批准号:
10598399 - 财政年份:2020
- 资助金额:
$ 18.53万 - 项目类别:
Pulmonary Hypertension Associated with Sickle Cell Disease
与镰状细胞病相关的肺动脉高压
- 批准号:
9251902 - 财政年份:2016
- 资助金额:
$ 18.53万 - 项目类别:
Impact of the micromechanical environment on inflammation in AAA progression
微机械环境对 AAA 进展中炎症的影响
- 批准号:
8766950 - 财政年份:2014
- 资助金额:
$ 18.53万 - 项目类别:
Right Ventricular-Pulmonary Vascular Interactions in Pulmonary Hypertension
肺动脉高压中右心室-肺血管的相互作用
- 批准号:
8317371 - 财政年份:2011
- 资助金额:
$ 18.53万 - 项目类别:
Right Ventricular-Pulmonary Vascular Interactions in Pulmonary Hypertension
肺动脉高压中右心室-肺血管的相互作用
- 批准号:
8184771 - 财政年份:2011
- 资助金额:
$ 18.53万 - 项目类别:
Right Ventricular-Pulmonary Vascular Interactions in Pulmonary Hypertension
肺动脉高压中右心室-肺血管的相互作用
- 批准号:
8528700 - 财政年份:2011
- 资助金额:
$ 18.53万 - 项目类别:
Vascular collagen accumulation & mechanical mechanisms in pulmonary hypertension
血管胶原蛋白堆积
- 批准号:
7822382 - 财政年份:2009
- 资助金额:
$ 18.53万 - 项目类别:
Collagen Accumulation & Mechanical Mechanisms in Pulmonary Hypertension
胶原蛋白堆积
- 批准号:
8912626 - 财政年份:2007
- 资助金额:
$ 18.53万 - 项目类别:
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