miRNA-mediated reduction of VSMC foam cell formation
miRNA 介导的 VSMC 泡沫细胞形成减少
基本信息
- 批准号:10376766
- 负责人:
- 金额:$ 53.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-23 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:Adaptor Signaling ProteinAnti-Inflammatory AgentsAntiinflammatory EffectApoptosisArterial Fatty StreakArteriesAtherosclerosisAttenuatedBlood VesselsCarotid ArteriesCell CycleCellsCholesterolDataDevelopmentDiseaseDown-RegulationEventFoam CellsFunctional disorderFundingGoalsHomeostasisHyperlipidemiaImmunohistochemistryInflammatoryKnockout MiceLigationLinkLipidsLow Density Lipoprotein ReceptorLow-Density LipoproteinsMedialMediatingMicroRNAsModelingMolecularMusMuscleMutationPathway interactionsPatientsPharmacotherapyPhenotypeProcessPublishingRegulationReportingRoleSmall Interfering RNASmooth Muscle MyocytesStimulusSyndromeTestingTherapeuticVascular DiseasesVascular ProliferationVascular Smooth MuscleWorkatherogenesisatheroprotectivecell injurycell typeconditional knockoutcytokinehypercholesterolemiain vivointerleukin-19macrophagenoveloxidized low density lipoproteinprotein protein interactionreceptorresponserestenosistransdifferentiationuptakevascular smooth muscle cell proliferation
项目摘要
The transformation of vascular smooth muscle cells (VSMC) into foam cells leading to increased plaque
size and decreased stability is a key, yet understudied step in atherogenesis. Our work in the previous
funding cycle (HL117724) demonstrated that Interleukin-19 (IL-19), a novel, anti-inflammatory cytokine,
attenuates atherosclerosis by multiple anti-inflammatory effects on VSMC as well as by increasing lipid
uptake and efflux in macrophage. In published and preliminary studies described here, we show that IL-19
reduces lipid accumulation in VSMC, an atheroprotective event, but without modifying expression of lipid
receptors or transporters. IL-19 induces expression of miR133a, a muscle-specific miRNA previously
ascribed to regulate VSMC phenotype. Although unrecognized and unreported, we have identified that
miR133a can target and reduce expression of Low Density Lipoprotein Receptor Adaptor Protein 1,
(LDLRAP1), an adaptor protein which functions to internalize the LDL receptor. Patients with mutations in
LDLRAP1 have LDL receptor malfunction leading to hyperlipidemia and Autosomal Recessive
Hypercholesterolemia (ARH) disorder. Nothing at all is known about a role for miR133a in regulation of
lipid uptake and development of atherosclerosis. Similarly, nothing at all has been published about
LDLRAP1 expression, function, and participation in VSMC foam cell formation. We have reported that that
both miR133a and LDLRAP1 regulate oxLDL uptake in VSMC. LDLRAP1 is induced in VSMC by oxLDL, is
not detectible in normal medial VSMC, but is expressed in plaque and neointimal VSMC of injured arteries.
IL-19 can reduce LDLRAP1 expression and oxLDL uptake in VSMC. Both miR133a and LDLRAP1regulate
VSMC proliferation, previously unrecognized functions for these molecules. Preliminary studies indicate
that the LDLRAP1+/- mouse has increased atherosclerosis, but reduced restenosis. In this competitive
renewal application, we hypothesize that LDLRAP1 can be selectively reduced in VSMC because miR133a
is muscle specific, and that reduction of lipid uptake by VSMC is atheroprotective and could also attenuate
vascular proliferative syndromes. The overall goals of this application are to determine causative roles for
miR133a and LDLRAP1 in VSMC lipid uptake, proliferation, atherogenesis, cholesterol-induced phenotype
modulation, and vascular restenosis.
血管平滑肌细胞(VSMC)转化为泡沫细胞导致斑块增加
项目成果
期刊论文数量(1)
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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MICHAEL V AUTIERI其他文献
MICHAEL V AUTIERI的其他文献
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{{ truncateString('MICHAEL V AUTIERI', 18)}}的其他基金
Regulation of adipose tissue microvascular function by IL19
IL19对脂肪组织微血管功能的调节
- 批准号:
10686973 - 财政年份:2022
- 资助金额:
$ 53.57万 - 项目类别:
Regulation of adipose tissue microvascular function by IL19
IL19对脂肪组织微血管功能的调节
- 批准号:
10503662 - 财政年份:2022
- 资助金额:
$ 53.57万 - 项目类别:
Interleukin-19 Inhibits Atherosclerosis by Diverse Mechanisms
Interleukin-19 通过多种机制抑制动脉粥样硬化
- 批准号:
8594550 - 财政年份:2013
- 资助金额:
$ 53.57万 - 项目类别:
Interleukin-19 Inhibits Atherosclerosis by Diverse Mechanisms
Interleukin-19 通过多种机制抑制动脉粥样硬化
- 批准号:
8705581 - 财政年份:2013
- 资助金额:
$ 53.57万 - 项目类别:
Interleukin-19 Inhibits Atherosclerosis by Diverse Mechanisms
Interleukin-19 通过多种机制抑制动脉粥样硬化
- 批准号:
8878340 - 财政年份:2013
- 资助金额:
$ 53.57万 - 项目类别:
Mechanisms of Th2 interleukin-driven angiogenesis
Th2白细胞介素驱动的血管生成机制
- 批准号:
8666808 - 财政年份:2013
- 资助金额:
$ 53.57万 - 项目类别:
Mechanisms of Th2 interleukin-driven angiogenesis
Th2白细胞介素驱动的血管生成机制
- 批准号:
8508007 - 财政年份:2013
- 资助金额:
$ 53.57万 - 项目类别:
Mechanisms of Th2 interleukin-driven angiogenesis
Th2白细胞介素驱动的血管生成机制
- 批准号:
8837059 - 财政年份:2013
- 资助金额:
$ 53.57万 - 项目类别:
Suppression of VSMC Activation and Mechanisms of Vascular Protection by IL-19
IL-19抑制VSMC激活及血管保护机制
- 批准号:
8071157 - 财政年份:2009
- 资助金额:
$ 53.57万 - 项目类别:
Suppression of VSMC Activation and Mechanisms of Vascular Protection by IL-19
IL-19抑制VSMC激活及血管保护机制
- 批准号:
7654035 - 财政年份:2009
- 资助金额:
$ 53.57万 - 项目类别:
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