A K63-Ubiquitination Dependent Necroptosis Signaling Network in the Heart
心脏中 K63 泛素化依赖性坏死性凋亡信号网络
基本信息
- 批准号:10090946
- 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:2021
- 资助国家:美国
- 起止时间:2021-01-08 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAcuteAddressAdultApoptosisAttenuatedBiologicalCardiacCardiac MyocytesCaspaseCell Death Signaling ProcessCell membraneCessation of lifeComplexDataDilated CardiomyopathyDiseaseEnzymesGene TransferGeneticGoalsHeartHeart InjuriesHeart failureInvestigationLinkMAP3K7 geneMediatingMitochondriaModelingMolecularMusMyocardialMyocardial IschemiaNecrosisOrganellesPathologicPathway interactionsPhosphorylationPhysiologyPilot ProjectsPlayPolyubiquitinationProcessRIPK1 geneRIPK3 geneRegulationReperfusion InjuryRoleSignal TransductionSwellingTNF receptor-associated factor 2TNFRSF1A geneTRAF2 geneTestingTherapeuticUbiquitinationcardioprotectionexperimental studygain of functionin vivoinsightischemic injurymyocardial injurynoveloverexpressionpreventreceptortherapeutic targetubiquitin ligaseubiquitin-protein ligasevector
项目摘要
Project Summary/Abstract
Loss of cardiomyocytes by apoptosis and/or necrosis is a hallmark of cardiac ischemic injury, pathological
remodeling, and end-stage heart failure. Although necrosis was traditionally regarded as a passive and
unregulated process, emerging evidence has shifted this paradigm and identified several forms of “programmed
necrosis”, including death receptor-mediated necrosis (termed “necroptosis”), mitochondria-mediated necrosis,
and other regulated necrotic processes. Despite recent progress, how necroptosis is regulated in the heart
remain largely unknown and preventing necroptotic cardiomyocyte death is still an important challenge. Our pilot
studies identified a new K63-linked polyubiquitination (K63-Ub) dependent necroptosis signaling network that
critically regulates cardiac ischemic injury and pathological remodeling. Intriguingly, the K63-deubiquitinase
CYLD (cylindromatosis) was markedly up-regulated, whereas the E3 ubiquitin ligase TRAF2 (TNF receptor
associated factor-2) was down-regulated, in the heart after ischemia-reperfusion injury. Our preliminary results
further identified CYLD and TRAF2 as an activator and a suppressor of myocardial necroptosis, respectively.
Importantly, cardiomyocyte-specific ablation of CYLD attenuated ischemic injury and adverse remodeling by
inhibiting necroptosis. Acute deletion of TRAF2 in the adult heart caused dilated cardiomyopathy by promoting
necroptosis, whereas TRAF2 gene transfer elicited cardioprotection. Mechanistically, we propose a new K63-
Ub dependent necroptotic regulatory mechanism whereby CYLD deubiquitinates TRAF2 and TAK1, disrupts
TAK1-RIP1 interaction, and promotes the necroptotic complex. As an opposing mechanism, TRAF2 acts as an
E3 ligase for TAK1 to inhibit necroptosis signaling. Thus, the reversible K63-Ub (mainly non-proteolytic)
constitutes a new paradigm of necroptosis signaling with important biological implications. We hypothesize
that the deubiquitinase CYLD, in conjunction with the E3 ligase TRAF2, critically regulate myocardial necroptosis,
ischemic injury, and remodeling, thus representing promising therapeutic targets. Aim 1 will investigate the
opposing roles of K63-Ub modifying enzymes CYLD and TRAF2 in regulating myocardial necroptosis and
ischemic injury in vivo. Aim 2 will define a CYLD/TRAF2 mediated, K63-Ub dependent necroptosis signaling
network in cardiomyocytes. Using genetic and molecular strategies, we will investigate the opposing roles of
CYLD and TRAF2 in regulating myocardial necroptosis under basal conditions and in the setting of ischemic
injury. The proposed studies will provide new insights into the molecular regulation and functional significance
of necroptosis in the heart, which has important translational implications, especially given our preliminary results
revealing CYLD/TRAF2 as key necroptotic regulators and promising targets for ischemic heart disease.
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)
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Qinghang Liu其他文献
Qinghang Liu的其他文献
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{{ truncateString('Qinghang Liu', 18)}}的其他基金
The Deubiquitinase CYLD Controls Multiple Cell Death Pathways in the Heart
去泛素酶 CYLD 控制心脏中的多种细胞死亡途径
- 批准号:
10545046 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
The Deubiquitinase CYLD Controls Multiple Cell Death Pathways in the Heart
去泛素酶 CYLD 控制心脏中的多种细胞死亡途径
- 批准号:
10332100 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
A K63-Ubiquitination Dependent Necroptosis Signaling Network in the Heart
心脏中 K63 泛素化依赖性坏死性凋亡信号网络
- 批准号:
10543111 - 财政年份:2021
- 资助金额:
$ 38.88万 - 项目类别:
A K63-Ubiquitination Dependent Necroptosis Signaling Network in the Heart
心脏中 K63 泛素化依赖性坏死性凋亡信号网络
- 批准号:
10327275 - 财政年份:2021
- 资助金额:
$ 38.88万 - 项目类别:
A Critical TAK1 Signaling Network in Myocardial Survival and Remodeling
心肌存活和重塑中关键的 TAK1 信号网络
- 批准号:
8606243 - 财政年份:2013
- 资助金额:
$ 38.88万 - 项目类别:
A Critical TAK1 Signaling Network in Myocardial Survival and Remodeling
心肌存活和重塑中关键的 TAK1 信号网络
- 批准号:
8417375 - 财政年份:2013
- 资助金额:
$ 38.88万 - 项目类别:
A Critical TAK1 Signaling Network in Myocardial Survival and Remodeling
心肌存活和重塑中关键的 TAK1 信号网络
- 批准号:
9187491 - 财政年份:2013
- 资助金额:
$ 38.88万 - 项目类别:
A Critical TAK1 Signaling Network in Myocardial Survival and Remodeling
心肌存活和重塑中关键的 TAK1 信号网络
- 批准号:
8770054 - 财政年份:2013
- 资助金额:
$ 38.88万 - 项目类别:
Role of TAK1 Signaling Network in Cardiac Hypertrophy
TAK1 信号网络在心脏肥大中的作用
- 批准号:
8235043 - 财政年份:2011
- 资助金额:
$ 38.88万 - 项目类别:
Role of TAK1 Signaling Network in Cardiac Hypertrophy
TAK1 信号网络在心脏肥大中的作用
- 批准号:
8231615 - 财政年份:2011
- 资助金额:
$ 38.88万 - 项目类别:
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