IL1beta signaling in SMCpromotes beneficial changes in late stage atherosclerotic lesion pathogenesis
IL1beta signaling in SMCpromotes beneficial changes in late stage atherosclerotic lesion pathogenesis
批准号:
10331329
负责人:
Gary K Owens
金额:
$76.87万
依托单位:
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:
2019-02-01 至 2024-01-31
关键词:
AddressAnti-Inflammatory AgentsAntibodiesAntibody TherapyApolipoprotein EApplications GrantsArterial Fatty StreakAtherosclerosisAttenuatedBlood VesselsCause of DeathCell LineageCellsClinicalClinical TrialsCollagenCoronary ArteriosclerosisCoronary arteryDevelopmentDisease ResistanceElderlyExtracellular MatrixGenesGenomicsHeart failureHumanHyperlipidemiaIL1R1 geneImmunoglobulin GImpairmentInflammationInflammatoryInterleukin-1 betaInterventionInvestmentsKnock-outLesionLesion by StageLife Style ModificationLigandsLipidsMaintenanceMedicineMicroscopicMusMyocardial InfarctionNatureNecrosisOutcomePathogenesisPathway interactionsPatientsPhenotypePlayProcessResolutionRoleRuptureSignal TransductionSiteSmooth Muscle MyocytesStem cell pluripotencyStimulusTamoxifenTestingTherapeuticThickThinnessTissuesatheroprotectiveatherothrombosisbiomarker panelcardiovascular disorder riskcell typechronic inflammatory diseasecohortconditional knockouteffective therapyexpectationfeedinghealingimprovedindexinginjury and repairinsightmacrophageneutralizing antibodypathogenprematurepreventreceptorresponsetraffickingwestern diet
中文摘要
动脉粥样硬化血栓形成是由不稳定的动脉粥样硬化斑块破裂或侵蚀引起的,是导致心脏病的主要原因
英文摘要
Atherothrombosis, resulting from rupture or erosion of unstable atherosclerotic plaques, is the leading cause of
death worldwide. However, the mechanisms that regulate the stability of late stage atherosclerotic lesions remain
poorly understood. The dogma is that: 1) plaques containing a large necrotic core, a thin fibrous cap, and large
numbers of CD68+ cells relative to Acta2+ cells [presumed to be macrophages (MФ) and smooth muscle cells
(SMC) respectively] are more prone to rupture; and 2) SMC play a beneficial role because they are the primary
cell type responsible for formation of a matrix-rich protective fibrous cap. However, recent studies by our lab
involving simultaneous SMC lineage tracing and SMC-specific knockout (KO) of the stem cell pluripotency genes
Oct4 or Klf4, provide compelling evidence challenging this dogma including showing that SMC can have major
beneficial or detrimental effects on late stage lesion pathogenesis depending on the nature of their phenotypic
transitions. As such, we sought to identify mechanisms to promote beneficial (atheroprotective) SMC phenotypic
transitions, and hypothesized that treatment with an anti-IL1β antibody (Ab) to globally suppress inflammation
would induce such changes. However, completely contrary to expectations, treatment of our SMC lineage-tracing
ApoE-/- mice with the anti-IL1β Ab between 18-26 weeks of Western diet resulted in multiple detrimental changes
including a marked reduction in fibrous cap thickness and collagen content, rapid loss of fibrous cap SMC and
replacement with MФs, and impaired outward remodeling. Studies in this proposal will test the hypothesis that
that IL1β signaling in SMC plays a critical beneficial role in late stage lesion pathogenesis including being
required for formation and maintenance of a protective fibrous cap. Aim 1 will determine if persistent IL1R1
signaling within SMC is required for maintenance of a SMC rich fibrous cap. Studies will include determining the
contributions of each of the IL1R1 ligands IL1β, and IL1α, as well as IL1Ra. We will also determine if SMC-
specific tamoxifen conditional KO of the IL1R1 receptor, after establishment of advanced atherosclerosis by 16-
18 weeks of WD feeding, results in loss of SMC fibrous cap coverage and other detrimental changes consistent
with plaque destabilization. Finally, we will determine if IL1β dependent phenotypic changes of SMC observed
in our mouse studies occur in human lesions and if these changes are predictive of plaque rupture or erosion.
Aim 2 will define critical variables and mechanisms that influence the effects of IL1β neutralization on late stage
lesion pathogenesis including those that may help to reconcile our findings with the recent positive outcomes of
the CANTOS Clinical Trial. This will include testing the hypotheses that the response to anti-IL1β therapy is
highly dependent on whether there is persistent hyperlipidemia/unresolved inflammation, and/or concurrent
myocardial infarction/heart failure. Taken together, the proposed studies will provide key insights regarding
fundamental mechanisms that regulate late stage lesion pathogenesis, and may contribute to development of
improved therapies for treating patients with advanced atherosclerosis.
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Response by Owens and Deaton to Letter Regarding Article, "Dichotomous Roles of Smooth Muscle Cell-Derived MCP1 (Monocyte Chemoattractant Protein 1) in Development of Atherosclerosis".
Owens 和 Deaton 对有关文章“平滑肌细胞衍生的 MCP1(单核细胞趋化蛋白 1)在动脉粥样硬化发展中的二分作用”的信件的回应。
DOI:
10.1161/atvbaha.122.318638
发表时间:
2023
期刊:
Arteriosclerosis, thrombosis, and vascular biology
影响因子:
--
作者:
[Owens,GaryK, Deaton,RebeccaA]
通讯作者:
Deaton,RebeccaA
DOI:
10.1161/atvbaha.120.315788
发表时间:
2021-07
期刊:
Arteriosclerosis, thrombosis, and vascular biology
影响因子:
--
作者:
[Cornelissen A, Fuller DT, Fernandez R, Zhao X, Kutys R, Binns-Roemer E, Delsante M, Sakamoto A, Paek KH, Sato Y, Kawakami R, Mori M, Kawai K, Yoshida T, Latt KZ, Miller CL, de Vries PS, Kolodgie FD, Virmani R, Shin MK, Hoek M, Heymann J, Kopp JB, Rosenberg AZ, Davis HR, Guo L, Finn AV]
通讯作者:
Finn AV
DOI:
10.1161/atvbaha.122.317882
发表时间:
2022-08
期刊:
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
影响因子:
8.7
作者:
[Owsiany, Katherine M., Deaton, Rebecca A., Soohoo, Karen G., Anh Tram Nguyen, Owens, Gary K.]
通讯作者:
Owens, Gary K.
DOI:
10.1161/atvbaha.120.314703
发表时间:
2021-01
期刊:
Arteriosclerosis, thrombosis, and vascular biology
影响因子:
--
作者:
[Bulut GB, Alencar GF, Owsiany KM, Nguyen AT, Karnewar S, Haskins RM, Waller LK, Cherepanova OA, Deaton RA, Shankman LS, Keller SR, Owens GK]
通讯作者:
Owens GK
DOI:
10.1172/jci.insight.154922
发表时间:
2023-03-08
期刊:
JCI INSIGHT
影响因子:
8
作者:
[Sakamoto, Atsushi, Kawakami, Rika, Mori, Masayuki, Guo, Liang, Paek, Ka Hyun, Mosquera, Jose Verdezoto, Cornelissen, Anne, Ghosh, Saikat Kumar B., Kawai, Kenji, Konishi, Takao, Fernandez, Raquel, Fuller, Daniela T., Xu, Weili, Vozenilek, Aimee E., Sato, Yu, Jinnouchi, Hiroyuki, Torii, Sho, Turner, Adam W., Akahori, Hirokuni, Kuntz, Salome, Weinkauf, Craig C., Lee, Parker J., Kutys, Robert, Harris, Kathryn, Killey, Alfred Lawrence, Mayhew, Christina M., Ellis, Matthew, Weinstein, Leah M., Gadhoke, Neel V., Dhingra, Roma, Ullman, Jeremy, Dikongue, Armella, Romero, Maria E., Kolodgie, Frank D., Miller, Clint I., Virmani, Renu, Finn, Aloke V.]
通讯作者:
Finn, Aloke V.
共 14 条
Role of IL-6 trans signaling in atherosclerosis development and late-stage pathogenesis
-
批准号:10652788
-
项目类别:
-
资助金额:$80.59万
-
财政年份:2023
-
负责人:Gary K Owens
-
依托单位:
Role of Smooth Muscle Cell Insulin Resistance and Systemic Metabolic Dysfunction in Atherosclerosis Development and Late Stage Lesion Pathogenesis
-
批准号:10731723
-
项目类别:
-
资助金额:$80.18万
-
财政年份:2023
-
负责人:Gary K Owens
-
依托单位:
Endothelial Cell to Mesenchymal Cell Transitions Play a Critical Biological Sex- and Aging-Dependent Role in Formation and Maintenance of the Acta2+ Atherosclerotic Lesion Protective Fibrous Cap
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批准号:10355596
-
项目类别:
-
资助金额:$79.29万
-
财政年份:2022
-
负责人:Gary K Owens
-
依托单位:
Endothelial Cell to Mesenchymal Cell Transitions Play a Critical Biological Sex- and Aging-Dependent Role in Formation and Maintenance of the Acta2+ Atherosclerotic Lesion Protective Fibrous Cap
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批准号:10542427
-
项目类别:
-
资助金额:$79.29万
-
财政年份:2022
-
负责人:Gary K Owens
-
依托单位:
Role of Metabolic Reprogramming in Formation and Maintenance of the Acta2+ Atherosclerotic Lesion Protective Fibrous Cap
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批准号:10441555
-
项目类别:
-
资助金额:$67.28万
-
财政年份:2021
-
负责人:Gary K Owens
-
依托单位:
Role of Metabolic Reprogramming in Formation and Maintenance of the Acta2+ Atherosclerotic Lesion Protective Fibrous Cap
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批准号:10612042
-
项目类别:
-
资助金额:$74.76万
-
财政年份:2021
-
负责人:Gary K Owens
-
依托单位:
Role of Metabolic Reprogramming in Formation and Maintenance of the Acta2+ Atherosclerotic Lesion Protective Fibrous Cap
-
批准号:10292012
-
项目类别:
-
资助金额:$74.76万
-
财政年份:2021
-
负责人:Gary K Owens
-
依托单位:
Defining SMC phenotypes critical in late stage atherosclerosis pathogenesis
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批准号:10084307
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项目类别:
-
资助金额:$74.09万
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财政年份:2018
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负责人:Gary K Owens
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依托单位:
Oct4 and Klf4 regulate microvascular SMC-pericyte plasticity, angiogenesis, and metabolic dysfunction
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批准号:9919376
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项目类别:
-
资助金额:$76.9万
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财政年份:2017
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负责人:Gary K Owens
-
依托单位:
PDGFbeta Receptor Activation Promotes Atheroprotective Changes in SMC Phenotype
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批准号:9908167
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项目类别:
-
资助金额:$65.2万
-
财政年份:2017
-
负责人:Gary K Owens
-
依托单位:
Oct4 and Klf4 regulate microvascular SMC-pericyte plasticity, angiogenesis, and metabolic dysfunction
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批准号:9378617
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项目类别:
-
资助金额:$76.68万
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财政年份:2017
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负责人:Gary K Owens
-
依托单位:
PDGFbeta Receptor Activation Promotes Atheroprotective Changes in SMC Phenotype
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批准号:9303020
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项目类别:
-
资助金额:$64.71万
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财政年份:2017
-
负责人:Gary K Owens
-
依托单位:
VASCULATA 2015
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批准号:8984946
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项目类别:
-
资助金额:$1.0万
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财政年份:2015
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负责人:Gary K Owens
-
依托单位:
Role of IL1b in Regulating SMC and Macrophage Differentiation in Atherosclerosis
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批准号:8609135
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项目类别:
-
资助金额:$56.06万
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财政年份:2013
-
负责人:Gary K Owens
-
依托单位:
Role of IL1b in Regulating SMC and Macrophage Differentiation in Atherosclerosis
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批准号:8974739
-
项目类别:
-
资助金额:$54.61万
-
财政年份:2013
-
负责人:Gary K Owens
-
依托单位:
Role of IL1b in Regulating SMC and Macrophage Differentiation in Atherosclerosis
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批准号:9178085
-
项目类别:
-
资助金额:$54.61万
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财政年份:2013
-
负责人:Gary K Owens
-
依托单位:
KLF4-Dependent Regulation of SMC Differentiation and Phenotypic Switching
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批准号:8012288
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项目类别:
-
资助金额:$67.5万
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财政年份:2010
-
负责人:Gary K Owens
-
依托单位:
KLF4-Dependent Regulation of SMC Differentiation and Phenotypic Switching
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批准号:7768056
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项目类别:
-
资助金额:$66.42万
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财政年份:2010
-
负责人:Gary K Owens
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依托单位:
KLF4-Dependent Regulation of SMC Differentiation and Phenotypic Switching
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批准号:8197627
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项目类别:
-
资助金额:$68.41万
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财政年份:2010
-
负责人:Gary K Owens
-
依托单位:
Role of Oxidized Phospholipids in Phenotypic Switching of Smooth Muscle Cells (SM
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批准号:7371716
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项目类别:
-
资助金额:$37.88万
-
财政年份:2008
-
负责人:Gary K Owens
-
依托单位:
海外基金