Mechanistic studies of disease progression in aortic aneurysms
Mechanistic studies of disease progression in aortic aneurysms
批准号:
10427154
负责人:
MEHRAN M SADEGHI
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-01-01 至 2023-06-30
关键词:
Abdominal Aortic AneurysmAddressAffectAneurysmAngiotensin IIAnimalsAortic AneurysmApolipoprotein EApolipoproteinsBiologyCalcium ChlorideCaliberCessation of lifeClinical ResearchClinical TrialsConflict (Psychology)DataDetectionDevelopmentDiseaseDisease ProgressionDoxycyclineEffectivenessElastasesElastinEvaluationEvolutionFutureGene DeletionGrowthHealthHealth Care CostsHigh PrevalenceHumanImageImaging TechniquesImmunityInflammationInflammatoryKnockout MiceKnowledgeLeadLinkLongitudinal StudiesMME geneMatrix Metalloproteinase InhibitorMatrix MetalloproteinasesMeasurementMedicalModelingMolecularMonitorMorbidity - disease rateMusNeutrophil InfiltrationOperative Surgical ProceduresPatientsPatternPlayPre-Clinical ModelResolutionRoleRuptureRuptured Abdominal Aortic AneurysmSmokerTestingTissuesVascular DiseasesVascular remodelingVeteransX-Ray Computed Tomographybasedisease heterogeneitydisease mechanisms studyimaging approachimprovedin vivoinhibitormacrophagemolecular imagingmortalitymouse modelmultimodalitynanoparticlenew therapeutic targetnon-drugnovelnuclear imagingpatient populationpreclinical studypreventrepairedrisk stratificationserial imagingspatial relationshiptherapeutic effectivenesstherapeutic targettooltreatment response
中文摘要
腹主动脉瘤(AAA)是退伍军人中的一种常见病,患病人数超过九分之一
英文摘要
Abdominal aortic aneurysm (AAA), a prevalent disease amongst veterans, affects more than 1 in 9
smokers and is responsible for 10,000 documented deaths every year in the US. AAA treatment remains
limited to surgical or endovascular repair for large aneurysms. This lack of an effective medical therapy reflects
existing gaps in knowledge regarding the molecular mechanisms of AAA, and lack of reliable tools for
evaluating vessel wall biology and monitoring therapeutic effectiveness in vivo. Several matrix
metalloproteinases (MMPs), including MMP-12 are upregulated in human AAA, and a number of MMPs have
been linked to AAA development. Elastin degradation is a key feature of aneurysm and MMP-12 is considered
the primary elastase in this setting. There are conflicting data regarding the role of MMP-12 in aneurysm
development and emerging information point to both anti- and pro-inflammatory functions for MMP-12 in
inflammatory disorders. This in conjunction with our preliminary data raise the intriguing hypothesis that MMP-
12 plays a dual role in aneurysm: inhibiting early stage aneurysm development through inhibition of neutrophil
recruitment to the vessel wall, and promoting expansion and rupture of established aneurysms by enhancing
vessel wall inflammation. Here, we introduce novel molecular imaging techniques for high resolution tracking of
vessel wall inflammation and MMP/MMP-12 imaging, which in conjunction with selective inhibitors and
knockout mice will be used to a) investigate the temporal and spatial pattern of MMP/MMP-12 activation in
relation to AAA development, progression and rupture; and b) address the role of MMP-12 in aneurysm.
Vascular remodeling will be tracked with high resolution multimodality molecular and structural imaging
followed by histomorphometric analysis in two complementary murine models, namely angiotensin II-induced
and calcium chloride-induced aneurysms. The temporal and spatial relationship between vessel wall biology,
response to therapy, and aneurysm expansion and rupture will be addressed through serial imaging in the
same animal. The effects of MMP-12 gene deletion and MMP-12 inhibition on aneurysm development, and
evolution of established aneurysms will be addressed. Combined, these studies will address novel aspects of
aneurysm pathobiology, validate novel therapeutic targets in preclinical models, and establish novel imaging
approaches for evaluation of vessel wall biology in aneurysms. Ultimately, this should lead to improved
management of patients with AAA (and possibly other vascular diseases); and reduce related morbidity,
mortality, and healthcare costs.
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DOI:
10.1021/acs.jmedchem.9b01186
发表时间:
2019-10
期刊:
Journal of medicinal chemistry
影响因子:
7.3
作者:
[Jakub Toczek;Thomas Bordenave;K. Gona;Hye-Yeong Kim;F. Beau;D. Georgiadis;Isabelle Correia;Y. Ye;Mahmoud Razavian;Jaejoon Jung;O. Lequin;V. Dive;M. Sadeghi;L. Devel]
通讯作者:
Jakub Toczek;Thomas Bordenave;K. Gona;Hye-Yeong Kim;F. Beau;D. Georgiadis;Isabelle Correia;Y. Ye;Mahmoud Razavian;Jaejoon Jung;O. Lequin;V. Dive;M. Sadeghi;L. Devel
DOI:
10.1016/j.jbiomech.2022.111179
发表时间:
2022-08
期刊:
JOURNAL OF BIOMECHANICS
影响因子:
2.4
作者:
[Spronck, Bart, Ramachandra, Abhay B., Moriyama, Lauren, Toczek, Jakub, Han, Jinah, Sadeghi, Mehran M., Humphrey, Jay D.]
通讯作者:
Humphrey, Jay D.
DOI:
10.7150/thno.55106
发表时间:
2021
期刊:
Theranostics
影响因子:
12.4
作者:
[Toczek J, Boodagh P, Sanzida N, Ghim M, Salarian M, Gona K, Kukreja G, Rajendran S, Wei L, Han J, Zhang J, Jung JJ, Graham M, Liu X, Sadeghi MM]
通讯作者:
Sadeghi MM
ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3.
DOI:
10.1016/j.canlet.2021.04.005
发表时间:
2021-07-10
期刊:
Cancer letters
影响因子:
9.7
作者:
[Coppo R, Orso F, Virga F, Dalmasso A, Baruffaldi D, Nie L, Clapero F, Dettori D, Quirico L, Grassi E, Defilippi P, Provero P, Valdembri D, Serini G, Sadeghi MM, Mazzone M, Taverna D]
通讯作者:
Taverna D
Molecular Imaging of Collagen Turnover in Cardiomyopathy
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批准号:10645228
-
项目类别:
-
资助金额:$79.57万
-
财政年份:2022
-
负责人:MEHRAN M SADEGHI
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依托单位:
Signal peptides and growth factor signaling
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批准号:10417764
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项目类别:
-
资助金额:$66.88万
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财政年份:2022
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负责人:MEHRAN M SADEGHI
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依托单位:
Molecular Imaging of Collagen Turnover in Cardiomyopathy
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批准号:10518655
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项目类别:
-
资助金额:$75.38万
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财政年份:2022
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负责人:MEHRAN M SADEGHI
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依托单位:
Signal peptides and growth factor signaling
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批准号:10586055
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项目类别:
-
资助金额:$66.88万
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财政年份:2022
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负责人:MEHRAN M SADEGHI
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依托单位:
Novel Regulators of Calcific Aortic Valve Disease
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批准号:9922787
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项目类别:
-
资助金额:$70.73万
-
财政年份:2017
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负责人:MEHRAN M SADEGHI
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依托单位:
Macrophage elastase and its imaging in vascular inflammation and remodeling
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批准号:8608590
-
项目类别:
-
资助金额:$51.64万
-
财政年份:2013
-
负责人:MEHRAN M SADEGHI
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依托单位:
Macrophage elastase and its imaging in vascular inflammation and remodeling
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批准号:9000577
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项目类别:
-
资助金额:$51.12万
-
财政年份:2013
-
负责人:MEHRAN M SADEGHI
-
依托单位:
Macrophage elastase and its imaging in vascular inflammation and remodeling
-
批准号:8796866
-
项目类别:
-
资助金额:$46.64万
-
财政年份:2013
-
负责人:MEHRAN M SADEGHI
-
依托单位:
Macrophage elastase and its imaging in vascular inflammation and remodeling
-
批准号:8438063
-
项目类别:
-
资助金额:$51.77万
-
财政年份:2013
-
负责人:MEHRAN M SADEGHI
-
依托单位:
Molecular Imaging of Protease Activation in Aneurysm
-
批准号:8439670
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2012
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负责人:MEHRAN M SADEGHI
-
依托单位:
Imaging protease activation in calcific aortic valve disease
-
批准号:9086412
-
项目类别:
-
资助金额:$41.63万
-
财政年份:2012
-
负责人:MEHRAN M SADEGHI
-
依托单位:
Imaging protease activation in calcific aortic valve disease
-
批准号:8352135
-
项目类别:
-
资助金额:$41.5万
-
财政年份:2012
-
负责人:MEHRAN M SADEGHI
-
依托单位:
Imaging protease activation in calcific aortic valve disease
-
批准号:8856329
-
项目类别:
-
资助金额:$41.0万
-
财政年份:2012
-
负责人:MEHRAN M SADEGHI
-
依托单位:
Imaging protease activation in calcific aortic valve disease
-
批准号:8535812
-
项目类别:
-
资助金额:$39.63万
-
财政年份:2012
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负责人:MEHRAN M SADEGHI
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依托单位:
Molecular Imaging of Protease Activation in Aneurysm
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批准号:8597944
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项目类别:
-
资助金额:$0.0万
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财政年份:2012
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负责人:MEHRAN M SADEGHI
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依托单位:
Imaging protease activation in calcific aortic valve disease
-
批准号:8697125
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项目类别:
-
资助金额:$40.79万
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财政年份:2012
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负责人:MEHRAN M SADEGHI
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依托单位:
Molecular Imaging of Vascular Remodeling
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批准号:7322418
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项目类别:
-
资助金额:$32.45万
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财政年份:2007
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负责人:MEHRAN M SADEGHI
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依托单位:
Molecular Imaging of Vascular Remodeling
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批准号:7874717
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项目类别:
-
资助金额:$32.45万
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财政年份:2007
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负责人:MEHRAN M SADEGHI
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依托单位:
Molecular Imaging of Vascular Remodeling
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批准号:7662509
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项目类别:
-
资助金额:$32.45万
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财政年份:2007
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负责人:MEHRAN M SADEGHI
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依托单位:
Molecular Imaging of Vascular Remodeling
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批准号:7487727
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项目类别:
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资助金额:$32.45万
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财政年份:2007
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负责人:MEHRAN M SADEGHI
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依托单位:
海外基金