Metabolic mechanisms of cardioprotection through alpha-1A adrenergic receptor activation
通过 α-1A 肾上腺素受体激活保护心脏的代谢机制
基本信息
- 批准号:10318139
- 负责人:
- 金额:$ 38.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-12-15 至 2022-11-30
- 项目状态:已结题
- 来源:
- 关键词:Adrenergic AgonistsAdrenergic ReceptorAdrenergic beta-AgonistsAffectAgonistAnimalsAttentionBindingBiological AssayCardiacCardiac MyocytesCatecholaminesCell DeathCellsCessation of lifeChronicClinical TreatmentClinical TrialsCoupledCouplingCytoprotectionDataDoxorubicinEchocardiographyEnzymesEpinephrineFunctional disorderFutureGene SilencingGenesGeneticGenetic TranscriptionGenus HippocampusGlucoseGlycolysisGoalsHeartHeart HypertrophyHeart failureHormonesHypertrophyImpairmentIn VitroInjuryIsoproterenolKnockout MiceLeadLightLong-Term EffectsMAP2K1 geneMAPK3 geneMEKsMediatingMetabolicMetabolismMitochondriaModelingModificationMolecularMusMyocardialNorepinephrineOralOxidative PhosphorylationPPAR gammaPathologicPathway interactionsPharmaceutical PreparationsPharmacologyPhenylephrinePlayPositron-Emission TomographyRadiolabeledReceptor ActivationRegulationRoleSignal PathwaySignal TransductionTestingToxic effectTreatment FailureUrinary IncontinenceVascular Smooth Musclealpha-1 adrenergic receptorsbeta-adrenergic receptorblood glucose regulationblood pressure elevationcardiogenesiscardioprotectionclinically relevantconstrictionexperimental studyfluorodeoxyglucose positron emission tomographyglucose metabolismheart preservationhemodynamicshexokinaseimprovedin vivoinhibitorinsightloss of functionmelanomamouse modelnovelnovel therapeuticsoxidationpreservationpreventprotective effectresponsesmall hairpin RNAvasoconstriction
项目摘要
PROJECT SUMMARY/ABSTRACT
Heart failure (HF) is characterized by markedly elevated levels of catecholamines that bind to adrenergic
receptors (ARs) in the heart. The toxic effects of excessive beta (β)-AR stimulation are well described, and
drugs that block β-ARs are cornerstones of contemporary HF therapy. Cardiac alpha (α)1-ARs have received
less attention, however data from cell and animal studies indicate that they protect against the development of
HF. There are two α1-AR subtypes in the heart: α1A, and α1B. The α1B mediates cardiac hypertrophy
induced by non-selective α1-AR agonists like phenylephrine. Activation of the α1A protects against
cardiomyocyte death and increases contractility in the failing heart, though the mechanisms underlying these
adaptive effects are poorly understood. We recently showed that an oral selective α1A agonist drug,
dabuzalgron, preserves ATP content and mitochondrial function in mouse HF models. These protective effects
were abrogated by trametinib, a MEK-ERK1/2 inhibitor used to treat melanoma. Our recent preliminary data
expand upon these novel findings by suggesting that α1A activation may improve cardiac energetics through
increased glucose utilization, coupling augmented glycolysis to glucose oxidation through enhanced oxidative
phosphorylation. The overarching hypothesis of this proposal is that α1A-ARs protect the failing heart through
an ERK1/2-mediated increase in glucose metabolism that counteracts the deleterious metabolic effects of
chronic β1 hyperstimulation in HF. In Aim 1, we will use a cardiomyocyte-specific α1A-AR knockout mouse in
two mouse models of pathological hypertrophy and HF to confirm the requirement of cardiomyocyte α1As for
the cardioprotective effects of dabuzalgron. In Aim 2, we will find if α1A-AR activation enhances glucose
utilization to provide energy for the failing heart using transverse aortic constriction in vivo coupled with in vitro
studies using selective pharmacology and gene silencing to identify key metabolic processes and signaling
pathways affected by α1A activation. Aim 3 will define the role of ERK1/2 activation in α1A-mediated
metabolic cardioprotection, using both trametinib and genetic modification of MEK-ERK axis to provide new
insights on the role of ERK1/2 signaling in the regulation of glucose metabolism and mitochondrial function.
Collectively the proposed experiments will expand our understanding of cardiac α1A-ARs and challenge the
prevailing paradigm that chronic catecholamine surge exerts uniformly deleterious effects in the failing heart.
项目总结/文摘
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
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 }}
Brian C Jensen其他文献
HIGH RESOLUTION MAPPING OF THE ALPHA-1A-ADRENERGIC RECEPTOR SUBTYPE IN MALE MOUSE UROGENITAL ORGANS
- DOI:
10.1016/s0022-5347(09)60425-0 - 发表时间:
2009-04-01 - 期刊:
- 影响因子:
- 作者:
Chihiro Hosoda;Bat-Erdene Myagmar;Philip M Swigart;Brian C Jensen;Paul C Simpson - 通讯作者:
Paul C Simpson
Brian C Jensen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('Brian C Jensen', 18)}}的其他基金
Defining the role of mitochondrial injury in MEK inhibitor cardiotoxicity
确定线粒体损伤在 MEK 抑制剂心脏毒性中的作用
- 批准号:
10753009 - 财政年份:2023
- 资助金额:
$ 38.88万 - 项目类别:
Metabolic mechanisms of cardioprotection through alpha-1A adrenergic receptor activation
通过 α-1A 肾上腺素受体激活保护心脏的代谢机制
- 批准号:
10587727 - 财政年份:2017
- 资助金额:
$ 38.88万 - 项目类别:
Metabolic mechanisms of cardioprotection through alpha-1A adrenergic receptor activation
通过 α-1A 肾上腺素受体激活保护心脏的代谢机制
- 批准号:
10067377 - 财政年份:2017
- 资助金额:
$ 38.88万 - 项目类别:
Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart
人类心脏细胞中的 Alpha-1-肾上腺素能受体亚型
- 批准号:
8131703 - 财政年份:2009
- 资助金额:
$ 38.88万 - 项目类别:
Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart
人类心脏细胞中的 Alpha-1-肾上腺素能受体亚型
- 批准号:
8496578 - 财政年份:2009
- 资助金额:
$ 38.88万 - 项目类别:
Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart
人类心脏细胞中的 Alpha-1-肾上腺素能受体亚型
- 批准号:
7707444 - 财政年份:2009
- 资助金额:
$ 38.88万 - 项目类别:
Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart
人类心脏细胞中的 Alpha-1-肾上腺素能受体亚型
- 批准号:
8294717 - 财政年份:2009
- 资助金额:
$ 38.88万 - 项目类别:
Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart
人类心脏细胞中的 Alpha-1-肾上腺素能受体亚型
- 批准号:
7919951 - 财政年份:2009
- 资助金额:
$ 38.88万 - 项目类别:
相似海外基金
Structural basis for regulation of beta2 adrenergic receptor signaling by the dynamic post-translational modification S-palmitoylation
动态翻译后修饰S-棕榈酰化调节β2肾上腺素受体信号传导的结构基础
- 批准号:
10603466 - 财政年份:2023
- 资助金额:
$ 38.88万 - 项目类别:
Modulation of T lymphocyte Activation by Ã2-Adrenergic Receptor Signalling Pathways
α2-肾上腺素能受体信号通路对 T 淋巴细胞激活的调节
- 批准号:
RGPIN-2019-06980 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
Discovery Grants Program - Individual
Glucocorticoid and Adrenergic Receptor Signaling at the Neuroimmune Interface
神经免疫界面的糖皮质激素和肾上腺素能受体信号传导
- 批准号:
RGPIN-2019-04706 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
Discovery Grants Program - Individual
Modulation of T lymphocyte Activation by ß2-adrenergic Receptor Signalling Pathways
α2-肾上腺素能受体信号通路对 T 淋巴细胞激活的调节
- 批准号:
574979-2022 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
University Undergraduate Student Research Awards
Angiotensin-(1-7) and beta adrenergic receptor signaling in aging
衰老过程中血管紧张素 (1-7) 和 β 肾上腺素受体信号传导
- 批准号:
10448574 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
Angiotensin-(1-7) and beta adrenergic receptor signaling in aging
衰老过程中血管紧张素 (1-7) 和 β 肾上腺素受体信号传导
- 批准号:
10629280 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
Novel regulation of beta-adrenergic receptor function by phosphoinositide 3-kinase
磷酸肌醇 3-激酶对 β-肾上腺素能受体功能的新调节
- 批准号:
10591688 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
Modulation of T lymphocyte Activation by Ã2-adrenergic Receptor Signalling Pathways
α2-肾上腺素能受体信号通路对 T 淋巴细胞激活的调节
- 批准号:
574984-2022 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
University Undergraduate Student Research Awards
Modulation of T lymphocyte Activation by ß2-adrenergic Receptor Signalling Pathways
α2-肾上腺素能受体信号通路对 T 淋巴细胞激活的调节
- 批准号:
574985-2022 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
University Undergraduate Student Research Awards
The molecular mechanism of the crosstalk between the beta-2 adrenergic receptor and chemokine receptors in lymphocytes
淋巴细胞β2肾上腺素受体与趋化因子受体串扰的分子机制
- 批准号:
22K07118 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
Grant-in-Aid for Scientific Research (C)