Cell-specific role and therapeutic potential of KCa3.1 in atherosclerosis
KCa3.1 在动脉粥样硬化中的细胞特异性作用和治疗潜力
基本信息
- 批准号:10586148
- 负责人:
- 金额:$ 55.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AngiographyAnimal ModelApolipoprotein EAreaArterial Fatty StreakAtherosclerosisBenignCalcium-Activated Potassium ChannelCause of DeathCellsCessation of lifeCharacteristicsClinicalClinical TrialsCoagulation ProcessCollagenComplexCoronaryCoronary AngiographyCoronary ArteriosclerosisCoronary heart diseaseDevelopmentDisease ProgressionDisease modelDrug TargetingFDA approvedFamilial HypercholesterolemiaFamily suidaeFoam CellsFoundationsGene ExpressionGenesGeneticGoalsHeart DiseasesHistologyHospitalsHumanImmunohistochemistryIn VitroInfiltrationInflammationInflammatoryInflammatory ResponseKnockout MiceLesionLinkMacrophageMammalsMedialMediatingMediatorModelingMusMyocardial InfarctionNecrosisOutcomePathogenesisPharmaceutical PreparationsPhenotypePlayProliferatingRegulator GenesReporterRoleRuptureSet proteinSignal TransductionSmooth MuscleSolidStrokeSymptomsTestingTherapeuticTomatoesTranslatingUnited Statesacute coronary syndromecell typecombatcoronary lesioncoronary plaquecostdrug testingin vivoinhibitormigrationmyocardinnext generationnovelpharmacologicporcine modelpre-clinicalrecruittherapeutically effectivetooltranscription factor RESTtranscriptome sequencingtransdifferentiationtranslational potentialultrasound
项目摘要
Pathogenesis of coronary artery disease is complex, with multiple cell types contributing to lesion size
and composition. Acute coronary syndromes are most often associated with rupture of complex,
vulnerable plaques that are otherwise clinically benign. The progression to either a relatively benign,
stable lesion or a rupture-prone, vulnerable plaque has been linked to key lesion characteristics, i.e.
smooth muscle (SM) and collagen content, macrophage infiltration and necrotic core area within the
lesion. The objectives of this proposal are to 1) determine the SM-specific role and underlying
mechanism(s) by which the intermediate conductance, Ca2+-activated K+ channel, KCa3.1 (encoded by
Kcnn4), dictates atherosclerotic lesion formation and composition and 2) determine the translational
potential of clinically approved KCa3.1 inhibitors on lesion development in a large mammal model of
coronary artery disease (CAD). In support, we provide the first genetic evidence of a causal link
between KCa3.1 and lesion size and SM and macrophage recruitment. The overall hypothesis is that
KCa3.1 activation increases migration of SM and macrophages into the intima and contributes to lesion
formation. Conversely, blocking KCa3.1, both by genetic silencing or pharmacologically, will decrease
atherosclerotic lesion size and beneficially alter composition. Aim 1 will determine the contribution of
KCa3.1 in smooth muscle to atherosclerotic lesion formation and composition. Specifically, we will use
SM-specific, inducible KO mice to examine the role of KCa3.1 in determining plaque size, composition
and gene expression. Aim 2 will define both upstream (REST) and downstream (DOCK2) mechanisms
determining KCa3.1 effects on SM and atherosclerosis. We will use genetically modified mice to
examine the role of REST and DOCK2 in mediating SM effects of KCa3.1 on phenotype, proliferation,
migration, plaque size and composition. In addition, we will use RNA sequencing to identify novel
mechanisms of atherosclerosis development by KCa3.1. We will use VSM lineage-tracking in Aim 3 will
use SM lineage-tracking to determine role of SMC-KCa3.1 in mediating SMC intimal to medial migration
and foam cell transdifferentiation during atherosclerotic lesion development. Finally, Aim 4 will
determine the effect of the FDA approved KCa3.1 inhibitor, senicapoc, on atherosclerosis development
in a swine model of CAD. We longitudinally track coronary artery disease progression using
angiography and IVUS in familial hypercholesterolemic (FH) swine to test the ability of KCa3.1 inhibition
with senicapoc, to decrease the size and promote a more favorable composition of coronary lesions.
The long-term goal is to provide the pre-clinical foundation for translating current therapeutic tools and
developing the next generation drugs targeting KCa3.1 and/or downstream signaling to beneficially
manipulate atherosclerotic lesion composition.
冠状动脉疾病的发病机制是复杂的,多种细胞类型有助于病变的大小
和组成。急性冠状动脉综合征最常与复杂的,
脆弱的斑块,否则临床上是良性的。无论是相对良性的,
稳定的病变或易破裂的易损斑块与关键病变特征有关,即,
平滑肌(SM)和胶原蛋白含量,巨噬细胞浸润和坏死核心区域内
损伤。本提案的目标是:1)确定工作人员-管理层的具体作用和基本职能;
中间电导,Ca 2+激活的K+通道,KCa3.1(由
Kcnn 4)决定动脉粥样硬化病变的形成和组成,2)确定翻译的
临床批准的KCa3.1抑制剂在大型哺乳动物模型中对病变发展的潜力
冠状动脉疾病(CAD)。作为支持,我们提供了第一个因果关系的遗传证据
KCa 3.1与病变大小和SM与巨噬细胞募集之间的关系。总的假设是,
KCa3.1激活增加SM和巨噬细胞向内膜的迁移并促成损伤
阵相反,通过基因沉默或抑制KCa3.1,
动脉粥样硬化病变大小和有益地改变组成。目标1将决定
KCa3.1在平滑肌中参与动脉粥样硬化病变的形成和组成。具体来说,我们将使用
SM特异性、诱导型KO小鼠,以检查KCa 3.1在确定斑块大小、组成
和基因表达。目标2将定义上游(REST)和下游(DOCK 2)机制
测定KCa 3.1对SM和动脉粥样硬化的作用。我们将用转基因老鼠
检查REST和DOCK 2在介导KCa 3.1对表型,增殖,
迁移、斑块大小和组成。此外,我们将使用RNA测序来鉴定新的
KCa3.1介导的动脉粥样硬化形成机制。我们将在Aim 3中使用VSM谱系跟踪
采用SM谱系追踪法检测SMC-KCa 3.1在介导SMC内膜向中膜迁移中的作用
和泡沫细胞转分化。最后,Aim 4将
确定FDA批准的KCa3.1抑制剂senicapoc对动脉粥样硬化发展的影响
在猪CAD模型中。我们纵向跟踪冠状动脉疾病的进展,
在家族性高胆固醇血症(FH)猪中进行血管造影和IVUS,以检测KCa 3.1抑制能力
与senicapoc,以减少冠状动脉病变的大小和促进更有利的组成。
长期目标是为转化当前的治疗工具提供临床前基础,
开发靶向KCa3.1和/或下游信号传导的下一代药物,
操纵动脉粥样硬化病变成分。
项目成果
期刊论文数量(0)
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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DOUGLAS K BOWLES其他文献
DOUGLAS K BOWLES的其他文献
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{{ truncateString('DOUGLAS K BOWLES', 18)}}的其他基金
Cell-specific role and therapeutic potential of KCa3.1 in atherosclerosis
KCa3.1 在动脉粥样硬化中的细胞特异性作用和治疗潜力
- 批准号:
10436073 - 财政年份:2022
- 资助金额:
$ 55.68万 - 项目类别:
Coronary ion channels, gender and vasoreactivity
冠状动脉离子通道、性别和血管反应性
- 批准号:
6900066 - 财政年份:2005
- 资助金额:
$ 55.68万 - 项目类别:
Ion Channel Regulation Coronary Smooth Muscle Phenotype
离子通道调节冠状动脉平滑肌表型
- 批准号:
7140016 - 财政年份:2005
- 资助金额:
$ 55.68万 - 项目类别:
Coronary ion channels, gender and vasoreactivity
冠状动脉离子通道、性别和血管反应性
- 批准号:
7596326 - 财政年份:2005
- 资助金额:
$ 55.68万 - 项目类别:
Coronary ion channels, gender and vasoreactivity
冠状动脉离子通道、性别和血管反应性
- 批准号:
7036585 - 财政年份:2005
- 资助金额:
$ 55.68万 - 项目类别:
Coronary ion channels, gender and vasoreactivity
冠状动脉离子通道、性别和血管反应性
- 批准号:
7367011 - 财政年份:2005
- 资助金额:
$ 55.68万 - 项目类别:
Coronary ion channels, gender and vasoreactivity
冠状动脉离子通道、性别和血管反应性
- 批准号:
7204177 - 财政年份:2005
- 资助金额:
$ 55.68万 - 项目类别:
Coronary ion channels, gender and vasoreactivity
冠状动脉离子通道、性别和血管反应性
- 批准号:
6820659 - 财政年份:2004
- 资助金额:
$ 55.68万 - 项目类别:
Coronary ion channels, gender and vasoreactivity
冠状动脉离子通道、性别和血管反应性
- 批准号:
6910679 - 财政年份:2004
- 资助金额:
$ 55.68万 - 项目类别:
Coronary ion channels, gender and vasoreactivity
冠状动脉离子通道、性别和血管反应性
- 批准号:
7440355 - 财政年份:2004
- 资助金额:
$ 55.68万 - 项目类别:
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