Defining SMC phenotypes critical in late stage atherosclerosis pathogenesis
Defining SMC phenotypes critical in late stage atherosclerosis pathogenesis
批准号:
10084307
负责人:
Gary K Owens
金额:
$74.09万
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
项目状态:
已结题
起止时间:
2018-01-01 至 2022-12-31
关键词:
AgeAnti-Inflammatory AgentsAortic SegmentApolipoprotein A-IApolipoprotein EArterial Fatty StreakAtherosclerosisBiological AssayCETP geneCause of DeathCell LineageCellsClinicalCollaborationsCollagenCoronary arteryDevelopmentDietEpigenetic ProcessEventGenesGenomicsGoalsHigh Density LipoproteinsHumanIn Situ HybridizationInflammatoryInvestmentsKnock-outLaboratoriesLeadLesionLesion by StageLigationLinkLipidsMechanicsMedicineMethodsModelingMusMyocardial InfarctionNatureNecrosisOperative Surgical ProceduresPathogenesisPharmaceutical PreparationsPhenotypePhenylephrinePlayProbabilityProgressive DiseaseResearchResolutionRiskRoleRuptureSmooth Muscle MyocytesStem cell pluripotencyStrokeTestingThickThinnessTransplantationVascular Smooth MuscleWestern Worldatheroprotectivebasebiomarker panelcell typeconditional knockoutcytokinefeedingin vivoindexinginhibitor/antagonistinnovationmacrophagenew therapeutic targetnovelnovel markernovel strategiesnovel therapeutic interventionrisk variantstem cellsthrombotictranscriptome sequencingvirtualwestern diet
中文摘要
点击翻译按钮获取中文摘要
英文摘要
Atherosclerosis is a progressive disease that is a leading cause of death in the Western world.
Remarkably, despite decades of research, there remain major ambiguities regarding the role of smooth
muscle cells (SMC) in lesion pathogenesis, as well as mechanisms that control plaque stability and the
probability of plaque rupture with possible myocardial infarction (MI) or stroke. The general dogma is that
SMC are primarily involved in late not early stage lesions, and that their primary role is atheroprotective
by contributing to formation of a fibrous cap. However, recent Nature Medicine studies by our lab involving
simultaneous SMC-specific lineage tracing and knockout (KO) of the stem cell pluripotency genes, Oct4
or Klf4 provided compelling evidence that SMC play a much greater role in lesion pathogenesis than has
been generally appreciated. Key findings included our showing that: 1) >80% of SMC-derived cells within
advanced lesions of ApoE-/- mice lack detectable expression of typical SMC markers; 2) 30-40% of SMC-
derived cells within both advanced mouse and human lesions lack detectable SMC markers and have
activated markers of MФs; and 3) SMC can have major beneficial or detrimental effects on lesion
pathogenesis depending on the nature of their phenotypic transitions. Studies in this proposal will test
the hypothesis that SMC phenotypic transitions can exert dominant atheroprotective or atheropromoting
effects on late stage lesion pathogenesis and represent a novel therapeutic target for treating advanced
atherosclerosis. Aim 1 will test the hypothesis that Klf4-dependent transitions in SMC phenotype and function
exacerbate lesion pathogenesis in early and late stages of atherosclerosis, and will include defining distinct
atheroprotective SMC phenotypes induced by SMC-specific conditional KO of Klf4 based on complementary flow
cytometric and high resolution confocal analyses of unique marker panels derived from our in vivo RNAseq and
Klf4/Oct4 ChIPseq genomic analyses of advanced brachiocephalic (BCA) lesions and cross referenced to genes
linked to increased human CAD risk. We will also determine if delayed SMC specific conditional KO of Klf4 after
establishment of advanced lesions also induces favorable changes in lesion pathogenesis. Aim 2 will test the
hypothesis that Oct4-dependent transitions in SMC phenotype and function promote plaque stabilization by
enhancing investment of SMC into a protective fibrous cap and reducing their transition to a pro-inflammatory
state. We will also test if SMC phenotypes identified in our mouse studies also occur in human lesions and define
which phenotypes correlate with stable versus unstable lesions. Aim 3 will determine if SMC phenotypic changes
within advanced lesions are reversible, and if treatment SMC lineage tracing mice with advanced lesions with a
PCSK9 inhibitor promotes beneficial changes in SMC phenotype and/or overall lesion pathogenesis. Studies may
lead to identification of novel therapeutic approaches for reducing late stage clinical complications of
atherosclerosis by inducing beneficial (plaque stabilizing) changes in SMC phenotype and function.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1080/15476286.2022.2141938
发表时间:
2022-01
期刊:
RNA BIOLOGY
影响因子:
4.1
作者:
[Mehlferber, Madison M., Jeffery, Erin D., Saquing, Jamie, Jordan, Ben T., Sheynkman, Leon, Murali, Mayank, Genet, Gael, Acharya, Bipul R., Hirschi, Karen K., Sheynkman, Gloria M.]
通讯作者:
Sheynkman, Gloria M.
DOI:
10.3389/fcvm.2023.1276945
发表时间:
2023
期刊:
FRONTIERS IN CARDIOVASCULAR MEDICINE
影响因子:
3.6
作者:
[Shin, Junchul, Tkachenko, Svyatoslav, Gomez, Delphine, Tripathi, Rupande, Owens, Gary K., Cherepanova, Olga A.]
通讯作者:
Cherepanova, Olga A.
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
-
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
-
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
-
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
-
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:
IL1beta signaling in SMCpromotes beneficial changes in late stage atherosclerotic lesion pathogenesis
-
批准号:10331329
-
项目类别:
-
资助金额:$76.87万
-
财政年份:2019
-
负责人:Gary K Owens
-
依托单位:
Oct4 and Klf4 regulate microvascular SMC-pericyte plasticity, angiogenesis, and metabolic dysfunction
-
批准号:9919376
-
项目类别:
-
资助金额:$76.9万
-
财政年份:2017
-
负责人:Gary K Owens
-
依托单位:
PDGFbeta Receptor Activation Promotes Atheroprotective Changes in SMC Phenotype
-
批准号:9908167
-
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
-
批准号:9378617
-
项目类别:
-
资助金额:$76.68万
-
财政年份:2017
-
负责人:Gary K Owens
-
依托单位:
PDGFbeta Receptor Activation Promotes Atheroprotective Changes in SMC Phenotype
-
批准号:9303020
-
项目类别:
-
资助金额:$64.71万
-
财政年份:2017
-
负责人:Gary K Owens
-
依托单位:
VASCULATA 2015
-
批准号:8984946
-
项目类别:
-
资助金额:$1.0万
-
财政年份:2015
-
负责人:Gary K Owens
-
依托单位:
Role of IL1b in Regulating SMC and Macrophage Differentiation in Atherosclerosis
-
批准号:8609135
-
项目类别:
-
资助金额:$56.06万
-
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
-
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
-
批准号:9178085
-
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:
KLF4-Dependent Regulation of SMC Differentiation and Phenotypic Switching
-
批准号:8012288
-
项目类别:
-
资助金额:$67.5万
-
财政年份:2010
-
负责人:Gary K Owens
-
依托单位:
KLF4-Dependent Regulation of SMC Differentiation and Phenotypic Switching
-
批准号:7768056
-
项目类别:
-
资助金额:$66.42万
-
财政年份:2010
-
负责人:Gary K Owens
-
依托单位:
KLF4-Dependent Regulation of SMC Differentiation and Phenotypic Switching
-
批准号:8197627
-
项目类别:
-
资助金额:$68.41万
-
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
-
批准号:7371716
-
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