Targeting the Inflammasome to Prevent Thoracic Aortic Aneurysms and Dissections
针对炎症小体预防胸主动脉瘤和夹层
基本信息
- 批准号:9247885
- 负责人:
- 金额:$ 39.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2020-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAneurysmAortic AneurysmAortic DiseasesBiomechanicsBone MarrowCASP1 geneCadeCardiovascular DiseasesCaspaseCause of DeathCellsCellular StressCessation of lifeChestCleaved cellContractile ProteinsDataDevelopmentDiseaseDisease ProgressionDissectionEventExtracellular MatrixFailureFunctional disorderGlyburideGoalsHospitalsHumanIn VitroIncidenceInfiltrationInflammasomeInflammationInflammatoryLifeMedialMediatingMissionModernizationMolecularMultiprotein ComplexesMusMyosin Heavy ChainsNational Heart, Lung, and Blood InstituteOperative Surgical ProceduresPatientsPeptide HydrolasesPharmacologyPlayPreventionPrevention strategyProceduresProteinsPublic HealthResearchRiskRoleSeriesSmooth Muscle MyocytesStressStructureTestingTherapeutic AgentsThoracic Aortic AneurysmThoracic aortaTimeTissuesTreatment EfficacyTropomyosinUnited StatesWild Type MouseWorkbasebiological adaptation to stressexperimental studyimprovedinhibitor/antagonistinnovationmortalitymouse modeloutcome forecastparthenolidepreventpublic health relevancerepairedtherapeutic targettreatment strategy
项目摘要
DESCRIPTION (provided by applicant): Ascending thoracic aortic aneurysms and dissections (ATAAD) are interrelated cardiovascular diseases that carry high mortality.] Current approaches to pharmacologic prevention of ATAAD are ineffective, particularly in patients with sporadic disease. Although there is a critical need to develop new treatment strategies, a major barrier to this goal is a poor understanding of the molecular mechanisms that trigger and then promote aortic degeneration in sporadic ATAAD. Therefore, our long-term goal is to improve the under- standing of the pathobiology of aortic wall degeneration in hope of developing new pharmacological strategies to prevent ATAAD formation and progression. The overall objective of this application is to systematically define the role of the NLRP3 inflammasome cascade, a multiprotein platform involved in amplifying intracellular stress responses, in promoting aortic destruction and the extent to which this cascade represents a therapeutic target against ATAAD. The central hypotheses are: (1) the NLRP3-ASC-caspase-1 cascade promotes aortic degeneration by promoting smooth muscle cell contractile dysfunction and aortic destruction, and (2) treatment with pharmacological inhibitors of this cascade will prevent ATAAD. These central hypotheses will be tested through three specific aims, each of which focuses on specific hypotheses based on our preliminary data. [In the first aim, we will seek to prove our hypothesis that the NLRP3- ASC-caspase-1 inflammasome cascade promotes ascending aortic wall inflammatory cell infiltration, matrix destruction, contractile dysfunction, and biomechanical failure through a series of experiments with a mouse model of sporadic ATAAD. In the second aim, we will seek to prove the hypothesis that the inflammasome cascade directly cleaves and degrades myosin heavy chain and tropomyosin, and thus promotes SMC contractile dysfunction. We will also determine whether intracellular stress activates the inflammasome cascade and confirm the association of intracellular stress and the inflammasome in human ATAAD tissue. In the third aim, we will test the hypothesis that NLRP3 inhibitors (glyburide, parthenolide and MCC950) will prevent ascending aortic destruction and disease progression in our mouse model of sporadic ATAAD.] The proposed research is significant because it will determine how the inflammasome cascade is activated, how this cascade promotes ATAAD development, and the extent to which an inflammasome inhibitor can prevent ATAAD. This research is innovative because it represents a new and substantive departure from the status quo, namely the current pharmacologic approaches to preventing aortic disease progression. The development of a new, effective pharmacological prevention strategy would have an important positive effect on disease prognosis by delaying or obviating invasive procedures in patients presenting with early-stage ascending aortic disease, suppressing disease progression in patients who are poor candidates for surgical treatment, and improving the durability of surgical aortic repairs.
描述(由申请人提供):胸主动脉瘤和夹层 (ATAAD) 是相互关联的心血管疾病,死亡率很高。] 目前 ATAAD 的药物预防方法无效,特别是对于散发性疾病的患者。尽管迫切需要开发新的治疗策略,但实现这一目标的一个主要障碍是对触发并促进散发性 ATAAD 的主动脉变性的分子机制了解甚少。因此,我们的长期目标是提高对主动脉壁变性病理学的认识,希望开发新的药理学策略来预防 ATAAD 的形成和进展。本申请的总体目标是系统地定义 NLRP3 炎性体级联(一种参与放大细胞内应激反应、促进主动脉破坏的多蛋白平台)的作用,以及该级联在多大程度上代表 ATAAD 的治疗靶点。中心假设是:(1) NLRP3-ASC-caspase-1 级联通过促进平滑肌细胞收缩功能障碍和主动脉破坏来促进主动脉变性,(2) 使用该级联的药物抑制剂治疗将预防 ATAAD。这些中心假设将通过三个具体目标进行检验,每个目标都侧重于基于我们初步数据的具体假设。 [第一个目标是,我们将通过散发性 ATAAD 小鼠模型的一系列实验来证明我们的假设,即 NLRP3-ASC-caspase-1 炎症小体级联促进升主动脉壁炎症细胞浸润、基质破坏、收缩功能障碍和生物力学衰竭。在第二个目标中,我们将寻求证明炎症小体级联直接裂解和降解肌球蛋白重链和原肌球蛋白,从而促进 SMC 收缩功能障碍的假设。我们还将确定细胞内应激是否激活炎症小体级联反应,并确认细胞内应激与人 ATAAD 组织中炎症小体的关联。在第三个目标中,我们将测试以下假设:NLRP3 抑制剂(格列本脲、小白菊内酯和 MCC950)将在我们的散发性 ATAAD 小鼠模型中预防升主动脉破坏和疾病进展。] 拟议的研究意义重大,因为它将确定炎性体级联如何被激活,该级联如何促进 ATAAD 发展,以及炎性体抑制剂可以在多大程度上预防 ATAAD。这项研究具有创新性,因为它代表了对现状(即当前预防主动脉疾病进展的药理学方法)的新的实质性偏离。开发一种新的、有效的药物预防策略将对疾病预后产生重要的积极影响,因为可以延迟或避免早期升主动脉疾病患者的侵入性操作,抑制不适合手术治疗的患者的疾病进展,并提高主动脉修复手术的耐久性。
项目成果
期刊论文数量(0)
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SCOTT A LEMAIRE其他文献
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{{ truncateString('SCOTT A LEMAIRE', 18)}}的其他基金
Pro-inflammatory Pyroptotic Cell Death in Aortic Degeneration
主动脉变性中的促炎焦亡细胞死亡
- 批准号:
10643934 - 财政年份:2021
- 资助金额:
$ 39.63万 - 项目类别:
Pro-inflammatory Pyroptotic Cell Death in Aortic Degeneration
主动脉变性中的促炎焦亡细胞死亡
- 批准号:
10435503 - 财政年份:2021
- 资助金额:
$ 39.63万 - 项目类别:
Pro-inflammatory Pyroptotic Cell Death in Aortic Degeneration
主动脉变性中的促炎焦亡细胞死亡
- 批准号:
10237565 - 财政年份:2021
- 资助金额:
$ 39.63万 - 项目类别:
Mitochondrial Damage-Induced Necroptotic Cell Death in SporadicAscending Thoracic Aortic Aneurysms and Dissections
散发性升主动脉瘤和夹层中线粒体损伤诱导的坏死性细胞死亡
- 批准号:
9765053 - 财政年份:2018
- 资助金额:
$ 39.63万 - 项目类别:
Mitochondrial Damage-Induced Necroptotic Cell Death in SporadicAscending Thoracic Aortic Aneurysms and Dissections
散发性升主动脉瘤和夹层中线粒体损伤诱导的坏死性细胞死亡
- 批准号:
9980977 - 财政年份:2018
- 资助金额:
$ 39.63万 - 项目类别:
Mitochondrial Damage-Induced Necroptotic Cell Death in SporadicAscending Thoracic Aortic Aneurysms and Dissections
散发性升主动脉瘤和夹层中线粒体损伤诱导的坏死性细胞死亡
- 批准号:
10239058 - 财政年份:2018
- 资助金额:
$ 39.63万 - 项目类别:
Targeting ER Stress To Treat Aortic Aneurysms and Dissections
针对内质网应激治疗主动脉瘤和夹层
- 批准号:
9338945 - 财政年份:2016
- 资助金额:
$ 39.63万 - 项目类别:
Targeting ER stress to Treat Aortic Aneurysms and Dissections
针对内质网应激治疗主动脉瘤和夹层
- 批准号:
9081997 - 财政年份:2016
- 资助金额:
$ 39.63万 - 项目类别:
Targeting the Inflammasome to Prevent Thoracic Aortic Aneurysms and Dissections
针对炎症小体预防胸主动脉瘤和夹层
- 批准号:
9130437 - 财政年份:2015
- 资助金额:
$ 39.63万 - 项目类别:
NATIONAL REGISTRY OF GENETICALLY TRIGGERED THORACIC AORTIC ANEURYSMS
国家基因触发胸主动脉瘤登记处
- 批准号:
8356739 - 财政年份:2010
- 资助金额:
$ 39.63万 - 项目类别:
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