Defining SMC phenotypes critical in late stage atherosclerosis pathogenesis
定义在晚期动脉粥样硬化发病机制中至关重要的 SMC 表型
基本信息
- 批准号:10084307
- 负责人:
- 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
- 起止时间:2018-01-01 至 2022-12-31
- 项目状态:已结题
- 来源:
- 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
项目摘要
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.
动脉粥样硬化是一种进行性疾病,是西方世界死亡的主要原因。
值得注意的是,尽管经过了几十年的研究,关于平滑的作用仍然存在很大的模糊性。
肌细胞(SMC)在病变发病机制中的作用,以及控制斑块稳定性和
斑块破裂的可能性,可能伴有心肌梗死(MI)或卒中。一般的教条是,
SMC主要参与晚期而非早期病变,其主要作用是动脉粥样硬化保护
通过促进纤维帽的形成。然而,我们实验室最近的自然医学研究,
同时SMC特异性谱系追踪和干细胞多能性基因敲除(KO),Oct4
或Klf4提供了令人信服的证据,表明SMC在病变发病机制中发挥的作用比
得到普遍赞赏。关键发现包括我们的研究结果:1)> 80%的SMC来源的细胞在
ApoE-/-小鼠的晚期病变缺乏典型SMC标志物的可检测表达; 2)30 - 40%的SMC-
晚期小鼠和人类病变中的衍生细胞缺乏可检测的SMC标记物,
活化的M β s标志物; 3)SMC可对病变产生主要的有益或有害影响,
发病机制取决于其表型转变的性质。本提案中的研究将测试
假设SMC表型转变可以发挥显性动脉粥样硬化保护或动脉粥样硬化促进作用,
对晚期病变发病机制的影响,并代表了治疗晚期病变的新治疗靶点。
动脉粥样硬化目的1将检验SMC表型和功能中Klf4依赖性转变的假设,
在动脉粥样硬化的早期和晚期加重病变的发病机制,并将包括定义不同的
SMC特异性Klf4条件性敲除诱导SMC表型保护作用的研究
对源自我们的体内RNAseq的独特标志物组进行细胞计数和高分辨率共聚焦分析,
晚期头臂型(BCA)病变的Klf4/Oct4 ChIPseq基因组分析和交叉参考基因
与人类CAD风险增加有关。我们还将确定Klf4的延迟SMC特异性条件性KO是否在
晚期病变的建立也引起病变发病机制的有利变化。目标2将测试
假设SMC表型和功能中Oct4依赖性转变通过以下方式促进斑块稳定
增强SMC向保护性纤维帽的投资,并减少其向促炎性细胞的转化,
状态我们还将测试在我们的小鼠研究中鉴定的SMC表型是否也发生在人类病变中,并确定
这些表型与稳定病变和不稳定病变相关。目的3将确定SMC表型是否发生变化
在晚期病变中,如果治疗晚期病变的SMC谱系示踪小鼠,
PCSK9抑制剂促进SMC表型和/或整体病变发病机制的有益变化。研究可能
导致识别用于减少晚期临床并发症的新的治疗方法,
动脉粥样硬化通过诱导SMC表型和功能的有益(斑块稳定)变化。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Characterization of protein isoform diversity in human umbilical vein endothelial cells via long-read proteogenomics.
- DOI:10.1080/15476286.2022.2141938
- 发表时间:2022-01
- 期刊:
- 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.
Smooth muscle cells-specific loss of OCT4 accelerates neointima formation after acute vascular injury.
- DOI:10.3389/fcvm.2023.1276945
- 发表时间:2023
- 期刊:
- 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.
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Gary K Owens其他文献
Gary K Owens的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Gary K Owens', 18)}}的其他基金
Role of IL-6 trans signaling in atherosclerosis development and late-stage pathogenesis
IL-6反式信号传导在动脉粥样硬化发展和晚期发病机制中的作用
- 批准号:
10652788 - 财政年份:2023
- 资助金额:
$ 74.09万 - 项目类别:
Role of Smooth Muscle Cell Insulin Resistance and Systemic Metabolic Dysfunction in Atherosclerosis Development and Late Stage Lesion Pathogenesis
平滑肌细胞胰岛素抵抗和全身代谢功能障碍在动脉粥样硬化发展和晚期病变发病机制中的作用
- 批准号:
10731723 - 财政年份:2023
- 资助金额:
$ 74.09万 - 项目类别:
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
内皮细胞向间充质细胞的转变在 Acta2 动脉粥样硬化病变保护性纤维帽的形成和维持中发挥着关键的生物性别和衰老依赖性作用
- 批准号:
10355596 - 财政年份:2022
- 资助金额:
$ 74.09万 - 项目类别:
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
内皮细胞向间充质细胞的转变在 Acta2 动脉粥样硬化病变保护性纤维帽的形成和维持中发挥着关键的生物性别和衰老依赖性作用
- 批准号:
10542427 - 财政年份:2022
- 资助金额:
$ 74.09万 - 项目类别:
Role of Metabolic Reprogramming in Formation and Maintenance of the Acta2+ Atherosclerotic Lesion Protective Fibrous Cap
代谢重编程在 Acta2 动脉粥样硬化病变保护性纤维帽形成和维持中的作用
- 批准号:
10441555 - 财政年份:2021
- 资助金额:
$ 74.09万 - 项目类别:
Role of Metabolic Reprogramming in Formation and Maintenance of the Acta2+ Atherosclerotic Lesion Protective Fibrous Cap
代谢重编程在 Acta2 动脉粥样硬化病变保护性纤维帽形成和维持中的作用
- 批准号:
10612042 - 财政年份:2021
- 资助金额:
$ 74.09万 - 项目类别:
Role of Metabolic Reprogramming in Formation and Maintenance of the Acta2+ Atherosclerotic Lesion Protective Fibrous Cap
代谢重编程在 Acta2 动脉粥样硬化病变保护性纤维帽形成和维持中的作用
- 批准号:
10292012 - 财政年份:2021
- 资助金额:
$ 74.09万 - 项目类别:
IL1beta signaling in SMCpromotes beneficial changes in late stage atherosclerotic lesion pathogenesis
SMC 中的 IL1β 信号传导促进晚期动脉粥样硬化病变发病机制的有益变化
- 批准号:
10331329 - 财政年份:2019
- 资助金额:
$ 74.09万 - 项目类别:
Oct4 and Klf4 regulate microvascular SMC-pericyte plasticity, angiogenesis, and metabolic dysfunction
Oct4 和 Klf4 调节微血管 SMC-周细胞可塑性、血管生成和代谢功能障碍
- 批准号:
9919376 - 财政年份:2017
- 资助金额:
$ 74.09万 - 项目类别:
PDGFbeta Receptor Activation Promotes Atheroprotective Changes in SMC Phenotype
PDGFbeta 受体激活促进 SMC 表型的动脉粥样硬化变化
- 批准号:
9908167 - 财政年份:2017
- 资助金额:
$ 74.09万 - 项目类别:
相似海外基金
Development of small molecule inhibitors as anti-inflammatory agents and antidotes for arsenicals
开发作为抗炎剂和砷解毒剂的小分子抑制剂
- 批准号:
10727507 - 财政年份:2023
- 资助金额:
$ 74.09万 - 项目类别:
Discovery of New Anti-Inflammatory Agents to Treat COPD
发现治疗慢性阻塞性肺病的新型抗炎药
- 批准号:
9194162 - 财政年份:2016
- 资助金额:
$ 74.09万 - 项目类别:
Synthesis of anti-inflammatory agents and their structure-activity relationships studies
抗炎药的合成及其构效关系研究
- 批准号:
496858-2016 - 财政年份:2016
- 资助金额:
$ 74.09万 - 项目类别:
University Undergraduate Student Research Awards
NAAA Inhibitors as Anti-inflammatory Agents, Phase II
NAAA 抑制剂作为抗炎剂,II 期
- 批准号:
9201955 - 财政年份:2015
- 资助金额:
$ 74.09万 - 项目类别:
Novel flavonoids as anti-inflammatory agents in alcoholism
新型黄酮类化合物作为酒精中毒的抗炎剂
- 批准号:
8251289 - 财政年份:2014
- 资助金额:
$ 74.09万 - 项目类别:
TLR-7 Agonists as Targeted Anti-inflammatory Agents in Arthritis
TLR-7 激动剂作为关节炎的靶向抗炎药
- 批准号:
8302750 - 财政年份:2012
- 资助金额:
$ 74.09万 - 项目类别:
Design and in vivo delivery of novel anti-inflammatory agents
新型抗炎剂的设计和体内递送
- 批准号:
267940 - 财政年份:2012
- 资助金额:
$ 74.09万 - 项目类别:
Operating Grants
Development of inlammasome inhibitors to be used as anti-inflammatory agents
开发用作抗炎剂的inlammasome抑制剂
- 批准号:
8403458 - 财政年份:2012
- 资助金额:
$ 74.09万 - 项目类别:
Development of inlammasome inhibitors to be used as anti-inflammatory agents
开发用作抗炎剂的inlammasome抑制剂
- 批准号:
8549297 - 财政年份:2012
- 资助金额:
$ 74.09万 - 项目类别:
TLR-7 Agonists as Targeted Anti-inflammatory Agents in Arthritis
TLR-7 激动剂作为关节炎的靶向抗炎药
- 批准号:
8472443 - 财政年份:2012
- 资助金额:
$ 74.09万 - 项目类别: