Pro-inflammatory Pyroptotic Cell Death in Aortic Degeneration
主动脉变性中的促炎焦亡细胞死亡
基本信息
- 批准号:10435503
- 负责人:
- 金额:$ 60.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AminesAortaAortic DiseasesAortic InjuryApoptosisAtherosclerosisBiomechanicsCardiovascular DiseasesCause of DeathCell DeathCell membraneCellsClinicalCytosolDNADNA DamageDNA-dependent protein kinaseDataDevelopmentDiabetic AngiopathiesDilatation - actionDiseaseDisease ProgressionDissectionEmergency SituationEventExtracellular MatrixExtravasationFailureGenerationsGenetic DiseasesGoalsHeart failureHypertensionIn VitroInflammationInflammatoryKnockout MiceLearningLifeLinkMarfan SyndromeMediatingMissionMitochondriaModelingMolecularMusNational Heart, Lung, and Blood InstituteNecrosisOperative Surgical ProceduresOxidative StressPathogenesisPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPhosphotransferasesPreventionPublic HealthResearchRoleRuptureSeriesSignal PathwaySignal TransductionSmooth Muscle MyocytesStimulator of Interferon GenesSting InjuryStructureTBK1 geneTestingThoracic Aortic AneurysmTissuesUnited StatesVDAC1 geneVascular DiseasesWorkascending aortabaseexperimental studyimprovedin vivoinhibitorknock-downmouse modelnovelpreventsensortherapeutic targettreatment strategy
项目摘要
Project Summary
Ascending thoracic aortic aneurysms and dissections (ATAAD), either associated with genetic conditions or
spontaneous as sporadic ATAAD, are extremely lethal diseases that often present as surgical emergencies.
Unfortunately, no clinically proven medication is available to prevent sporadic ATAAD progression. There is a
critical need to develop effective pharmacological strategies to treat ATAAD. The hallmark of sporadic ATAAD
is progressive aortic smooth muscle cell (SMC) depletion and extracellular matrix (ECM) destruction leading to
aortic dilatation, dissection, and ultimately rupture. Our long-term goal is to improve our understanding of the
molecular pathogenesis of sporadic ATAAD in hope of developing new pharmacological strategies to prevent
disease progression. Our preliminary studies suggest that damaged DNA in SMCs activates a pore-forming
protein, gasdermin D (GSDMD), that drives SMC pyroptosis, an inflammatory form of programmed cell death
that may represent a common pathway to aortic SMC loss. Therefore, the objectives of this application are to
determine the role and mechanisms of GSDMD-mediated SMC pyroptosis in ATAAD development and to ex-
amine the extent to which cytosolic DNA sensing and pyroptosis represent therapeutic targets against ATAAD.
Our central hypothesis is that sensor pathways triggered by damaged DNA activate GSDMD-mediated SMC
pyroptosis, leading to aortic degeneration, dissection, and rupture. In Aim 1, we will determine the role of
GSDMD-mediated SMC pyroptosis in ATAAD formation. We will test the hypothesis that GSDMD-mediated
SMC pyroptosis is critically involved in aortic degeneration, biomechanical failure, and ATAAD development by
examining these aspects in Gsdmd-/-mice and inducible SMC-specific Gsdmd knockout mice in our established
sporadic ATAAD model. In Aim 2, we will investigate the mechanisms underlying the activation of GSDMD-
mediated SMC pyroptosis. In a series of in vitro and in vivo experiments, we will test the hypothesis that cyto-
solic DNA-triggered cGAS-STING sensor signaling, through TBK1/IKK2/DNA-PK kinases, directly phosphory-
lates GSDMD and promotes its activation and pore formation in plasma membranes, leading to mitochondrial
damage and ultimately pyroptotic SMC death. In Aim 3, we will determine the extent to which suppressing cy-
tosolic DNA sensing and pyroptotic cell death will prevent ATAAD development and progression. We will test
the hypothesis that simultaneously blocking the cGAS-STING pathway and pyroptosis will prevent aortic de-
struction and disease progression in our sporadic ATAAD model. We expect that this work will determine how
damaged DNA induces pyroptosis and thereby compromises the structure and function of the ascending aortic
wall. The positive impact of this work will be an improved understanding of the molecular mechanisms that
cause SMC pyroptosis in the development of aortic degeneration, providing an exciting new direction for treat-
ment strategies for preventing ATAAD formation and its fatal sequelae. The novel mechanisms regarding DNA
damage-induced pyroptotic cell death will also have broad implications in many other cardiovascular diseases.
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项目总结
项目成果
期刊论文数量(0)
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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:
$ 60.11万 - 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:
$ 60.11万 - 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:
$ 60.11万 - 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:
$ 60.11万 - 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:
$ 60.11万 - 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:
9247885 - 财政年份:2016
- 资助金额:
$ 60.11万 - 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:
$ 60.11万 - 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:
$ 60.11万 - 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:
$ 60.11万 - 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:
$ 60.11万 - 项目类别:
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