Proteoglycan dynamics in pathogenesis of thoracic aortic aneurysm and dissection
胸主动脉瘤和夹层发病机制中的蛋白多糖动力学
基本信息
- 批准号:9769293
- 负责人:
- 金额:$ 40万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-15 至 2020-08-31
- 项目状态:已结题
- 来源:
- 关键词:ADAMTSADAMTS1 geneAdhesionsAdhesivesAffectAgeAneurysmAortaAortic DiseasesAreaBiological MarkersBiomechanicsBloodBlood CirculationBlood VesselsCarbohydratesCartilageCell AdhesionCell ShapeCell physiologyCellsChondroitin SulfatesCleaved cellClinicClinicalCollagenCytoskeletonDataDefectDiagnosisDiseaseDissectionElastic FiberElastinEnzymesExtracellular MatrixFBN1Functional disorderGenesGeneticHandHealthHistologyHomeostasisHumanHyaluronanImpairmentIndividualKnowledgeLeftLifeMaintenanceMarfan SyndromeMechanicsMedialMediatingMessenger RNAModelingMonitorMusMutateNamesOutcomePathogenesisPathogenicityPathologicPathway interactionsPatient-Focused OutcomesPeptide HydrolasesPhenotypeProcessPropertyProteinsProteoglycanProteolysisResearchResistanceRoleScientistSeverity of illnessShapesSiteSmooth Muscle MyocytesStainsStress FibersStructureSurgeonSwellingTestingThoracic Aortic AneurysmTissuesTransforming Growth Factor betaTunica MediaUp-RegulationVascular Smooth MuscleWorkaggrecanascending aortabasebiomedical referral centercell dedifferentiationextracellularimproved outcomeinsightinterstitialknock-downmechanotransductionmouse modelneglectnon-geneticnovelnovel markerpotential biomarkerpressurepreventprospectiverelating to nervous systemresponsetandem mass spectrometrytargeted treatmenttreatment centerversican
项目摘要
SUMMARY: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening manifestation of diverse
vascular smooth muscle cell (VSMC) or extracellular matrix (ECM) disorders. The histopathological hallmark of
TAAD is aortic medial degeneration (AMD), characterized by proteoglycan accumulation (pooling), elastic fiber
fragmentation and VSMC degeneration. Proteoglycan pools alter aorta biomechanics and facilitate dissection
by raising focal tissue swelling pressure within the aortic wall but have been neglected. Their precise
composition, their cellular impact and potential as a target for therapy are unexplored. We hypothesize that
accumulation of the large aggregating proteoglycans aggrecan and versican is a consistent pathologic feature
of TAAD, alters VSMC phenotype and survival to compromise aorta function, and could arise from reduced
proteolysis. We will ask: Is aggrecan and versican accumulation a consistent feature of human TAAD
regardless of primary cause, and are they indicators of disease severity? Does their accumulation result from
reduced ADAMTS protease activity in addition to mRNA upregulation such as following TGFβ dysregulation,
commonly seen in TAAD? What are other components of the proteoglycan pools in AMD? What impact does
aggrecan and versican accumulation have on VSMC? Would their reduction prevent or ameliorate TAAD?
Proteoglycan profiling of the normal human aorta and TAAD aorta by tandem mass spectrometry identified 20
proteoglycans, including versican, long known to be an important vascular component, and aggrecan,
traditionally regarded as a cartilage and neural component. Immunostaining of normal and TAAD ascending
aortas collected prospectively at the Cleveland Clinic revealed an unexpected, massive increase of aggrecan
and versican in TAAD aortas. Aggrecan accumulated in TAA in a mouse model of Marfan syndrome, and both
aggrecan and versican in mice haploinsufficient for the aggrecan/versican degrading protease, ADAMTS1.
The specific aims are: 1. To characterize proteoglycan dysregulation in human TAAD using quantitative
tandem mass spectrometry approaches and investigate its correlation to disease severity. 2. To determine the
pathogenic mechanisms by which reduced proteoglycan turnover by ADAMTS1 contributes to TAAD and the
impact of excess aggrecan on VSMC function. 3. To test whether genetic deletion of aggrecan and/or versican
prevents TAA and/or dissection in mouse models of Marfan syndrome and Adamts1-haploinsufficient mice.
Impact: In addition to new fundamental knowledge of aortic ECM dynamics and cell-matrix interactions, the
work will identify mechanisms that predispose the aortic wall to aneurysms and/or dissection, provide novel
biomarkers for diagnosis and monitoring of TAAD, and identify pathways that could be targeted in non-surgical
management of TAAD.
摘要:胸主动脉瘤及夹层(TAAD)是一种多种危及生命的表现
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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SUNEEL S APTE其他文献
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{{ truncateString('SUNEEL S APTE', 18)}}的其他基金
The proteolytic landscape of osteoarthritic cartilage
骨关节炎软骨的蛋白水解景观
- 批准号:10606642 
- 财政年份:2022
- 资助金额:$ 40万 
- 项目类别:
The proteolytic landscape of osteoarthritic cartilage
骨关节炎软骨的蛋白水解景观
- 批准号:10370498 
- 财政年份:2022
- 资助金额:$ 40万 
- 项目类别:
Extracellular matrix remodeling in ocular anterior segment development
眼前节发育中的细胞外基质重塑
- 批准号:8798380 
- 财政年份:2014
- 资助金额:$ 40万 
- 项目类别:
Extracellular matrix remodeling in ocular anterior segment development
眼前节发育中的细胞外基质重塑
- 批准号:9189617 
- 财政年份:2014
- 资助金额:$ 40万 
- 项目类别:
American Society for Matrix Biology Biennial Meeting 2014
2014 年美国基质生物学学会双年会
- 批准号:8785810 
- 财政年份:2014
- 资助金额:$ 40万 
- 项目类别:
2013 Matrix Metalloproteinase Gordon Research Conference and Gordon Research Semi
2013年基质金属蛋白酶戈登研究会议及戈登研究半会
- 批准号:8511050 
- 财政年份:2013
- 资助金额:$ 40万 
- 项目类别:
Endothelial protease activity, organogenesis and birth defects
内皮蛋白酶活性、器官发生和出生缺陷
- 批准号:8318871 
- 财政年份:2011
- 资助金额:$ 40万 
- 项目类别:
Endothelial protease activity, organogenesis and birth defects
内皮蛋白酶活性、器官发生和出生缺陷
- 批准号:8177298 
- 财政年份:2011
- 资助金额:$ 40万 
- 项目类别:

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