Metabolic control in vascular remodeling
血管重塑中的代谢控制
基本信息
- 批准号:10543542
- 负责人:
- 金额:$ 59.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAffectAnimalsAortaAreaArterial InjuryArteriesArteriosclerosisAspartateAtherosclerosisBiological AssayBlood VesselsCadherinsCardiovascular DiseasesCause of DeathCell ProliferationCell WallCell divisionCell physiologyCellsCellular Metabolic ProcessCellular biologyComplexDNA DamageDataDevelopmentDiseaseDorsalElementsEmbryoEmbryonic DevelopmentEndothelial CellsExtracellular MatrixFAT geneFrequenciesFunctional disorderGeneticGoalsGrowthHealthHomeostasisImpairmentInjuryInterventionInvadedKnowledgeLabelLongevityMediatingMetabolic ControlMetabolismMitochondriaMitochondrial DNAModelingMusNADH dehydrogenase (ubiquinone)NeuronsObstructionOxidative PhosphorylationOxygen ConsumptionPathogenesisPathogenicityPathologyPhenotypePlayPopulationPredispositionPreventiveProcessProliferatingProteinsReactive Oxygen SpeciesRegulationResearchRespirationRoleSmooth Muscle MyocytesStructureTestingTherapeuticTimeTissue EngineeringTransplantationTubeVascular DiseasesVascular Smooth MuscleVascular remodelingVascularizationangiogenesiscell behaviorcell growthclinically significantcytokinedisabilityin vivomechanical forcemetabolic phenotypemigrationmouse developmentmouse modelnoveloxidationpharmacologicpostnatalpreventrepairedrespiratoryresponserestenosisrestraintscreeningtherapeutic angiogenesistumorvascular injuryvasculogenesis
项目摘要
Summary
Vascular remodeling is essential for artery formation during embryogenesis and in the
pathogenesis of vascular diseases such as atherosclerosis, restenosis, and transplant-
associated arteriosclerosis in adulthood. Despite this high clinical significance, our incomplete
understanding of the process of vascular remodeling limits current abilities to develop
preventive and therapeutic strategies. Vascular smooth muscle cells (SMCs) are main drivers of
developmental and adult vascular remodeling, but mechanisms underlying SMC activities are
not fully elucidated — in particular, the role of mitochondria and metabolism in this context is
relatively unexplored. The goal of this proposal is to understand mitochondrion-based
mechanisms that regulate SMC phenotype in vascular remodeling. We have shown that the
FAT1 cadherin interacts with and inhibits mitochondrial respiratory complex I, limits SMC
proliferation by restraining mitochondrial respiration, and opposes vascular occlusion after
arterial injury. These findings suggest that respiratory complex I regulates SMC behavior. Our
new preliminary data further support this idea. Loss of complex I subunit NDUFS4 in cultured
SMCs decreases complex I levels and activity, limits the formation of supercomplexes
containing complex I, lowers aspartate levels, and impairs cell growth. In vivo, NDUFS4 is highly
expressed during mouse development in SMCs building the arterial wall, and in adult mice in
SMC-derived cells that form the expanding neointima that accumulates in response to arterial
injury. Preliminary studies with selective NDUFS4 deletion in SMCs suggest that these cells
require respiratory complex I for normal embryogenesis. We hypothesize that complex I
promotes SMC activities important for vascular remodeling during embryogenesis and in
adulthood. We will test this hypothesis in three specific aims that respectively address the
effects of impaired respiratory complex I function 1) on key SMC activities, 2) on mouse
vascular development, and 3) in models of adult vascular homeostasis, injury, and
atherosclerotic disease. These studies will add a new respiratory complex-based angle —
susceptible to pharmacological intervention — to our understanding of how arteries form and
how they respond to injury, with relevance for tissue engineering, therapeutic angiogenesis,
tumor vascularization, and vascular disease.
总结
血管重塑是胚胎发育过程中动脉形成所必需的,
血管疾病的发病机制,如动脉粥样硬化、再狭窄和移植-
与成年期动脉硬化有关。尽管有很高的临床意义,我们的不完整
对血管重塑过程的理解限制了目前发展
预防和治疗策略。血管平滑肌细胞(SMC)是血管平滑肌细胞的主要驱动力。
发育和成人血管重塑,但SMC活动的机制是
没有完全阐明-特别是,线粒体和代谢在这种情况下的作用,
相对未开发。本提案的目标是了解基于Linux的
在血管重塑中调节SMC表型的机制。我们已经证明,
FAT 1钙粘蛋白与线粒体呼吸复合物I相互作用并抑制,限制SMC
增殖,抑制线粒体呼吸,并反对血管闭塞后,
动脉损伤这些发现表明,呼吸复合物I调节SMC的行为。我们
新的初步数据进一步支持这一观点。培养的细胞中复合物I亚基NDUFS 4的丢失
SMC降低复合物I水平和活性,限制超复合物的形成
含有复合物I,降低天冬氨酸水平,并损害细胞生长。在体内,NDUFS 4是高度
在小鼠发育过程中,在构建动脉壁的SMC中表达,在成年小鼠中,
SMC衍生的细胞形成扩张的新生内膜,其响应于动脉粥样硬化而积聚。
损伤SMCs中选择性NDUFS 4缺失的初步研究表明,这些细胞
需要呼吸复合物I来进行正常的胚胎发生。我们假设复合物I
促进SMC活性,这对胚胎发生过程中的血管重塑和
成年我们将在三个具体目标中检验这一假设,
呼吸复合物I功能受损的影响:1)对关键SMC活性,2)对小鼠
血管发育,和3)成人血管稳态,损伤,和
动脉粥样硬化性疾病这些研究将增加一个新的基于呼吸复合体的角度-
易受药物干预的影响-我们对动脉如何形成和
它们如何对损伤作出反应,与组织工程,治疗性血管生成,
肿瘤血管形成和血管疾病。
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)
Neutrophil extracellular traps in cardiac hypertrophy: a KLF2 perspective.
- DOI:10.1172/jci156453
- 发表时间:2022-02-01
- 期刊:
- 影响因子:0
- 作者:Riascos-Bernal DF;Sibinga NE
- 通讯作者:Sibinga NE
The FAT1 Cadherin Drives Vascular Smooth Muscle Cell Migration.
- DOI:10.3390/cells12121621
- 发表时间:2023-06-14
- 期刊:
- 影响因子:6
- 作者:Riascos-Bernal, Dario F.;Ressa, Gaia;Korrapati, Anish;Sibinga, Nicholas E. S.
- 通讯作者:Sibinga, Nicholas E. S.
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Nicholas E Sibinga其他文献
Nicholas E Sibinga的其他文献
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{{ truncateString('Nicholas E Sibinga', 18)}}的其他基金
Allograft inflammatory factor-1 and immune tolerance
同种异体移植物炎症因子-1和免疫耐受
- 批准号:
10511362 - 财政年份:2022
- 资助金额:
$ 59.36万 - 项目类别:
Allograft inflammatory factor-1 and immune tolerance
同种异体移植物炎症因子-1和免疫耐受
- 批准号:
10642960 - 财政年份:2022
- 资助金额:
$ 59.36万 - 项目类别:
Beta-catenin in vascular homeostasis and remodeling
β-连环蛋白在血管稳态和重塑中的作用
- 批准号:
9507901 - 财政年份:2017
- 资助金额:
$ 59.36万 - 项目类别:
Beta-catenin in vascular homeostasis and remodeling
β-连环蛋白在血管稳态和重塑中的作用
- 批准号:
9884555 - 财政年份:2017
- 资助金额:
$ 59.36万 - 项目类别:
Colony stimulating factor-1 in graft vascular disease
移植血管疾病中的集落刺激因子-1
- 批准号:
9276113 - 财政年份:2015
- 资助金额:
$ 59.36万 - 项目类别:
Allograft inflammatory factor-1 in atherosclerosis
同种异体移植物炎症因子-1在动脉粥样硬化中的作用
- 批准号:
8913555 - 财政年份:2015
- 资助金额:
$ 59.36万 - 项目类别:
Colony stimulating factor-1 in graft vascular disease
移植血管疾病中的集落刺激因子-1
- 批准号:
8985741 - 财政年份:2015
- 资助金额:
$ 59.36万 - 项目类别:
The Fat1 Cadherin in Atherosclerotic Vascular Disease
Fat1 钙粘蛋白在动脉粥样硬化性血管疾病中的作用
- 批准号:
8109076 - 财政年份:2011
- 资助金额:
$ 59.36万 - 项目类别:
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