Cardiac Pathophysiology of Proteasome Phosphoregulation
蛋白酶体磷酸调节的心脏病理生理学
基本信息
- 批准号:10435491
- 负责人:
- 金额:$ 36.75万
- 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:2020-08-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:26S proteasomeAdrenergic AgentsAgeAnimalsAntibodiesAttenuatedBasic ScienceCardiacCardiac MyocytesCardiac healthCause of DeathCellsCellular biologyChronicClinical ManagementColorCoupledCultured CellsCyclic AMPCyclic AMP-Dependent Protein KinasesDataDiagnosisDiseaseFunctional disorderFutureGenesGeneticGenetic ModelsGoalsHealthcareHeartHeart DiseasesHeart HypertrophyHeart failureInheritedKnock-inLifeLongevityMolecularMusMyocardialMyocardial InfarctionMyocardial IschemiaMyocardiumNatureNodalPathologicPathologyPathway interactionsPerformancePharmacologyPhosphorylationPhosphotransferasesPhysiologicalPhysiologyPilot ProjectsPlayProtein KinaseProteinsProteolysisQuality ControlRegulationReporterReportingResearchResearch Project GrantsRoleSeveritiesStressSystemTestingTherapeuticTimeTouch sensationTransgenic MiceUbiquitinVirulence FactorsWild Type MouseWorkbasebody systemconstrictiondisabilityheart functionhuman morbidityhuman mortalityin vivoinnovationmimicrymouse modelmulticatalytic endopeptidase complexnovel therapeutic interventionoverexpressionpressurepreventprotein activationprotein degradationproteostasisproteotoxicityresponsestressortandem mass spectrometrytoolvirtual
项目摘要
Heart disease is the leading cause of human mortality and morbidity. The ubiquitin-proteasome system (UPS)
is pivotal to protein quantity and quality control in the cell. UPS dysregulation, especially proteasome functional
insufficiency, plays a major role in the progression from a large subset of heart diseases to heart failure and,
accordingly, proteasome enhancement is implicated as a new strategy to treat heart disease with increased
proteotoxic stress (IPTS). To develop pharmacological means to enhance the proteasome, however, requires
understanding how proteasome activity is regulated as such regulatory mechanisms could potentially be
exploited to enhance the proteasome. Recent advances in cell biology show that phosphorylation of the
proteasome often increases proteasome activities but the in vivo physiological significance of proteasome
phosphoregulation has not been established. Thus, the goal of this project is to advance our understanding on
how specific proteasome phosphorylation regulates cardiac physiology and pathophysiology. Our pilot studies
have confirmed genetically in mice that phosphorylation of RPN6/PSMD11 at Ser14 is responsible for
proteasome activation by cAMP-dependent protein kinase (PKA). Our preliminary data further revealed that (1)
myocardial Ser14-phopshorylated Rpn6 (referred to as p-Rpn6) was markedly altered in mice with inherited
IPTS and mice subjected to myocardial ischemia or trans-aortic constriction (TAC) and (2) genetic blockade
and mimicry of p-Rpn6 substantially mitigated cardiac responses to various stressors. Hence, we propose to
test the central hypotheses that p-Rpn6 is essential to 26S Psm activation to meet the increased demand for
selective proteolysis in stressed cardiac muscle, via pursuit of these specific aims: (1) to determine the
necessity of p-Rpn6 in cardiac proteostasis and cardiac function at baseline, (2) to determine the role of
increased p-Rpn6 in the inherited heart disease with IPTS, and (3) to determine the role of increased p-Rpn6 in
an acquired heart disease with IPTS. New mouse models created with gene editing to block or mimic p-Rpn6,
as well as p-Rpn6 specific antibodies will be used along with a well-established UPS performance reporter.
Tandem mass-tags (TMT) based multiplexing coupled with tandem mass spectrometry will be used to profile
ubiquitinomes shaped by p-Rpn6 in stressed hearts. This research will provide the ultimate in vivo
demonstration for the molecular basis of PKA-elicited proteasome activation, determine unequivocally for the
first time the (patho)physiological significance of this key proteasome phosphoregulation in intact animals, and
illustrate whether this regulation can be exploited for therapeutic purposes.
心脏病是人类死亡和发病的主要原因。泛素-蛋白酶体系统(UPS)
对细胞中蛋白质的数量和质量控制至关重要。UPS失调,尤其是蛋白酶体功能
心功能不全,在从大部分心脏病发展为心力衰竭中起主要作用,
因此,蛋白酶体增强被认为是治疗心脏病的新策略,
蛋白毒性应激(IPTS)。然而,为了开发增强蛋白酶体的药理学手段,需要
了解蛋白酶体活性是如何调节的,因为这种调节机制可能是
用来增强蛋白酶体细胞生物学的最新进展表明,
蛋白酶体通常增加蛋白酶体活性,但蛋白酶体的体内生理意义
磷酸调节尚未建立。因此,本项目的目标是促进我们对
特异性蛋白酶体磷酸化如何调节心脏生理学和病理生理学。我们的试点研究
已经在小鼠中证实了RPN 6/PSMD 11在Ser 14处的磷酸化是导致
cAMP依赖性蛋白激酶(PKA)激活蛋白酶体。我们的初步数据进一步显示,(1)
心肌Ser 14-磷酸化Rpn 6(简称p-Rpn 6)在遗传性心肌病小鼠中显著改变,
IPTS和经受心肌缺血或经主动脉缩窄(TAC)和(2)基因阻断的小鼠
并且p-Rpn 6的模拟物基本上减轻了对各种应激源的心脏反应。因此,我们建议
检验中心假设,即p-Rpn 6对26 S Psm活化是必不可少的,以满足对
应激心肌中的选择性蛋白水解,通过追求这些特定的目标:(1)确定
p-Rpn 6在基线时心脏蛋白质稳态和心脏功能中的必要性,(2)确定
p-Rpn 6在伴有IPTS的遗传性心脏病中的作用,以及(3)确定p-Rpn 6在
患有IPTS的后天性心脏病通过基因编辑来阻断或模拟p-Rpn 6的新小鼠模型,
以及p-Rpn 6特异性抗体将沿着使用完善的UPS性能报告物。
将使用基于串联质量标签(TMT)的多路复用与串联质谱联用来分析
应激心脏中由p-Rpn 6形成的泛素组。这项研究将提供最终的体内
证明PKA引起的蛋白酶体激活的分子基础,明确确定
首次在完整动物中发现了这种关键蛋白酶体磷酸化调节的(病理)生理学意义,
说明这种调节是否可以用于治疗目的。
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 }}
XUEJUN WANG其他文献
XUEJUN WANG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('XUEJUN WANG', 18)}}的其他基金
Priming the proteasome to protect against aging and Alzheimer's disease
启动蛋白酶体以预防衰老和阿尔茨海默病
- 批准号:
10448146 - 财政年份:2022
- 资助金额:
$ 36.75万 - 项目类别:
Cardiac Pathophysiology of Proteasome Phosphoregulation
蛋白酶体磷酸调节的心脏病理生理学
- 批准号:
10224336 - 财政年份:2020
- 资助金额:
$ 36.75万 - 项目类别:
Cardiac Pathophysiology of Proteasome Phosphoregulation
蛋白酶体磷酸调节的心脏病理生理学
- 批准号:
10033517 - 财政年份:2020
- 资助金额:
$ 36.75万 - 项目类别:
Cardiac Pathophysiology of Proteasome Phosphoregulation
蛋白酶体磷酸调节的心脏病理生理学
- 批准号:
10627948 - 财政年份:2020
- 资助金额:
$ 36.75万 - 项目类别:
Molecular Pathogenesis of Protein Surplus Cardiomyopathy
蛋白质过剩心肌病的分子发病机制
- 批准号:
7822353 - 财政年份:2009
- 资助金额:
$ 36.75万 - 项目类别:
SD COBRE: UBIQUITIN-PROTEASOME IN CARDIAC REMODELING AND FAILURE
SD COBRE:泛素蛋白酶体在心脏重构和衰竭中的作用
- 批准号:
7720647 - 财政年份:2008
- 资助金额:
$ 36.75万 - 项目类别:
相似海外基金
Preclinical test for the efficacy of adrenergic agents in treatment of AD
肾上腺素能药物治疗AD疗效的临床前试验
- 批准号:
8358448 - 财政年份:2012
- 资助金额:
$ 36.75万 - 项目类别:
Preclinical test for the efficacy of adrenergic agents in treatment of AD
肾上腺素能药物治疗AD疗效的临床前试验
- 批准号:
8517552 - 财政年份:2012
- 资助金额:
$ 36.75万 - 项目类别:
MODULATING FLUID THERAPY WITH ADRENERGIC AGENTS AND CYCLIC AMP ENHANCERS IN
使用肾上腺素能药物和环放大器增强剂调节液体治疗
- 批准号:
7952159 - 财政年份:2009
- 资助金额:
$ 36.75万 - 项目类别:
THE EFFECT OF BETA-ADRENERGIC AGENTS AND FLUID THERAPY IN HUMANS
β-肾上腺素能药物和液体疗法对人体的影响
- 批准号:
7952152 - 财政年份:2009
- 资助金额:
$ 36.75万 - 项目类别:
MODULATING FLUID THERAPY WITH ADRENERGIC AGENTS AND CYCLIC AMP ENHANCERS IN
使用肾上腺素能药物和环放大器增强剂调节液体治疗
- 批准号:
7719194 - 财政年份:2008
- 资助金额:
$ 36.75万 - 项目类别:
THE EFFECT OF BETA-ADRENERGIC AGENTS AND FLUID THERAPY IN HUMANS
β-肾上腺素能药物和液体疗法对人体的影响
- 批准号:
7605416 - 财政年份:2007
- 资助金额:
$ 36.75万 - 项目类别:
MODULATING FLUID THERAPY WITH ADRENERGIC AGENTS AND CYCLIC AMP ENHANCERS IN
使用肾上腺素能药物和环放大器增强剂调节液体治疗
- 批准号:
7605425 - 财政年份:2007
- 资助金额:
$ 36.75万 - 项目类别:
THE EFFECT OF BETA-ADRENERGIC AGENTS AND FLUID THERAPY IN HUMANS
β-肾上腺素能药物和液体疗法对人体的影响
- 批准号:
7378753 - 财政年份:2006
- 资助金额:
$ 36.75万 - 项目类别:
Adrenergic Agents for Methamphetamine: Outpatient Trials
甲基苯丙胺肾上腺素药物:门诊试验
- 批准号:
6825160 - 财政年份:2004
- 资助金额:
$ 36.75万 - 项目类别:
ADRENERGIC AGENTS FOR CARDIOPULMONARY RESUSCITATION
用于心肺复苏的肾上腺素能药物
- 批准号:
2702283 - 财政年份:1997
- 资助金额:
$ 36.75万 - 项目类别: