The NRF2-p62 Axis in the Cross-Talk between Proteasomal and Lysosomal Degradation
The NRF2-p62 Axis in the Cross-Talk between Proteasomal and Lysosomal Degradation
批准号:
9891075
负责人:
Taixing Cui
金额:
$35.06万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-04-01 至 2022-03-31
关键词:
AdultAnimalsAntioxidantsAttenuatedBindingCardiacCardiac MyocytesCardiomyopathiesCause of DeathClinical ManagementCongestive Heart FailureDiagnosisDiseaseExcisionFeedbackFunctional disorderGTF2H1 geneGenesGeneticGenetic ModelsGoalsHealthcareHeartHeart DiseasesHeart InjuriesHeart failureImpairmentKnock-outLifeLinkLiteratureMeasuresMediatingMolecularMusMyocardialMyocardial dysfunctionOrganellesOutcomePathologyPathway interactionsPerformancePharmaceutical PreparationsPharmacologyPhasePilot ProjectsPlayProteasome InhibitionProteinsQuality ControlResearchResearch Project GrantsRoleStressSyndromeSystemTestingToxic effectTransgenic MiceTransgenic OrganismsUbiquitinUbiquitinated Protein DegradationUbiquitinationUp-Regulationcardiogenesisclinical translationconstrictionheart functionhuman morbidityhuman mortalityhypertensive heart diseasein vivoinnovationinsightmisfolded proteinmouse geneticsmulticatalytic endopeptidase complexnovelnovel therapeutic interventionnuclear factor-erythroid 2pressurepreventprogramsprotein aggregationprotein degradationsham surgerytranscription factorvirtual
中文摘要
心力衰竭是人类死亡和发病的主要原因,但无法治愈。蛋白质降解
泛素-蛋白酶体系统(UPS)和自噬-溶酶体途径(ALP)是心脏蛋白的关键
质量控制,其作用是使心肌细胞中错误折叠蛋白质的水平和毒性最小化。蛋白
UPS和ALP功能障碍导致的质量控制不足与心脏的发育有关
包括压力超负荷(PO)紊乱在内的各种心脏病导致的衰竭。蛋白酶体抑制
激活ALP,而ALP损伤可损害UPS性能,这表明一种复杂的相互作用
UPS和ALP功能障碍之间的联系然而,这种相互作用在患病的心脏和其潜在的
机制尚待确定。因此,本研究项目的长期目标是描绘
UPS-ALP串扰的分子基础。文献和我们的初步研究表明,NRF 2(核因子-
红细胞2相关因子2)及其靶基因p62/SQSTM 1可能在红细胞2相关因子2受损中起分子联系作用。
ALP功能不全的UPS性能,但这仍有待建立在心脏。因此,我们建议
确定Nrf 2-p62轴在压力超负荷心脏中调节ALP-UPS串扰的作用。的
待检验的中心假设是Nrf 2-p62轴的激活在细胞凋亡中起主要的介导作用。
压力超负荷心脏中ALP不足对UPS性能的损害我们将继续追求2
具体目标。目的1将确定Nrf 2在诱导心脏UPS损伤和适应不良中的作用。
在PO心脏中通过ALP损伤进行重构。目的2将研究Nrf 2在细胞中的作用机制,
加剧了ALP不足心脏的心脏损伤,验证了Nrf 2诱导p62的假设,
损害ALP缺乏心脏的UPS性能。该项目可能会提供新的机械见解,
UPS-ALP在心脏中相互作用,并建立了一个新的概念,即在激活Nrf 2的同时增强ALP是一种新的治疗方法。
比单独激活Nrf 2更好的治疗心脏病的策略。
英文摘要
Heart failure is a leading cause of human mortality and morbidity without a cure. Protein degradation by the
ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) is pivotal to cardiac protein
quality control which acts to minimize the level and toxicity of misfolded proteins in cardiomyocytes. Protein
quality control inadequacy resulting from UPS and ALP dysfunctions is implicated in the development of heart
failure from a variety of heart diseases including pressure overload (PO) disorders. Proteasome inhibition
activates ALP while ALP impairment can compromise UPS performance, suggesting an intricate interplay
between UPS and ALP dysfunctions. However, such interplay in diseased hearts and its underlying
mechanisms remain to be defined. Therefore the long term goal of this research project is to delineate the
molecular basis of UPS-ALP crosstalk. Literature and our pilot studies suggest that NRF2 (nuclear factor-
erythroid 2-related factor 2) and its target gene p62/SQSTM1 may act as a molecular link in the impairment of
UPS performance by ALP insufficiency but this remains to be established in the heart. Hence, we propose to
determine the role of the Nrf2-p62 axis in regulating ALP-UPS cross-talk in pressure overloaded hearts. The
central hypothesis to be tested is that activation of the Nrf2-p62 axis plays a major mediating role in the
impairment of UPS performance by ALP insufficiency in pressure overloaded hearts. We will pursue 2
specific aims. Aim 1 will determine the role of Nrf2 in the induction of cardiac UPS impairment and maladaptive
remodeling by ALP impairment in PO hearts. Aim 2 will investigate the molecular mechanism by which Nrf2
exacerbates cardiac injury in ALP insufficient hearts, testing the hypothesis that induction of p62 by Nrf2
impairs UPS performance in ALP deficient hearts. This project will likely provide new mechanistic insight into
UPS-ALP interplay in the heart and establish a new concept that enhancing ALP while activating Nrf2 is a
better strategy than Nrf2 activation alone for treating heart disease.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3389/fphys.2021.673145
发表时间:
2021
期刊:
Frontiers in physiology
影响因子:
4
作者:
[Wu W, Qin Q, Ding Y, Zang H, Li DS, Nagarkatti M, Nagarkatti P, Wang W, Wang X, Cui T]
通讯作者:
Cui T
Cyclin-dependent kinase (CDK)19-mediated vein graft intimal hyperplasia
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批准号:10664327
-
项目类别:
-
资助金额:$15.65万
-
财政年份:2023
-
负责人:Taixing Cui
-
依托单位:
Metabolic control of vascular smooth muscle cell plasticity
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批准号:10829610
-
项目类别:
-
资助金额:$48.62万
-
财政年份:2021
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负责人:Taixing Cui
-
依托单位:
Metabolic control of vascular smooth muscle cell plasticity
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批准号:10334766
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项目类别:
-
资助金额:$63.62万
-
财政年份:2021
-
负责人:Taixing Cui
-
依托单位:
To explore the potential of UCH-L1 as a novel therapeutic and diagnostic target in heart failure
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批准号:10709559
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项目类别:
-
资助金额:$0.0万
-
财政年份:2020
-
负责人:Taixing Cui
-
依托单位:
To explore the potential of UCH-L1 as a novel therapeutic and diagnostic target in heart failure
-
批准号:10467982
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项目类别:
-
资助金额:$0.0万
-
财政年份:2020
-
负责人:Taixing Cui
-
依托单位:
To explore the potential of UCH-L1 as a novel therapeutic and diagnostic target in heart failure
-
批准号:10011124
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2020
-
负责人:Taixing Cui
-
依托单位:
To explore the potential of UCH-L1 as a novel therapeutic and diagnostic target in heart failure
-
批准号:10490344
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2020
-
负责人:Taixing Cui
-
依托单位:
The NRF2-p62 Axis in the Cross-Talk between Proteasomal and Lysosomal Degradation
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批准号:9311709
-
项目类别:
-
资助金额:$36.24万
-
财政年份:2017
-
负责人:Taixing Cui
-
依托单位:
A novel approach for transforming decelluarized vessel grafts into small-diameter arteries
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批准号:9317769
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项目类别:
-
资助金额:$16.69万
-
财政年份:2017
-
负责人:Taixing Cui
-
依托单位:
UBIQUITIN CARBOXYL TERMINAL HYDROLASE L1 (UCH-L1) AND VASCULAR LESION FORMATION
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批准号:8167799
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项目类别:
-
资助金额:$2.5万
-
财政年份:2010
-
负责人:Taixing Cui
-
依托单位:
American Ginseng-mediated Autophagy and Suppression of Inflammation (Project 3)
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批准号:8733732
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项目类别:
-
资助金额:$20.55万
-
财政年份:--
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负责人:Taixing Cui
-
依托单位:
American Ginseng-mediated Autophagy and Suppression of Inflammation (Project 3)
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批准号:8460788
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项目类别:
-
资助金额:$20.55万
-
财政年份:--
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负责人:Taixing Cui
-
依托单位:
American Ginseng-mediated Autophagy and Suppression of Inflammation (Project 3)
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批准号:8531299
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项目类别:
-
资助金额:$19.83万
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财政年份:--
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负责人:Taixing Cui
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依托单位:
海外基金