Cardiomyocyte CaM kinase II as a driver of cardiac inflammation and remodeling
心肌细胞 CaM 激酶 II 作为心脏炎症和重塑的驱动因素
基本信息
- 批准号:10308392
- 负责人:
- 金额:$ 39.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-12-15 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:AdultAnti-Inflammatory AgentsAttenuatedBiological AssayCCL2 geneCa(2+)-Calmodulin Dependent Protein KinaseCardiacCardiac MyocytesCause of DeathCellsDevelopmentFailureFibrosisFlow CytometryFunctional disorderGene DeletionGene ExpressionGenerationsGenetic TranscriptionGoalsGrowthHeartHeart DiseasesHeart failureHypertrophyImmuneImmunohistochemistryIn Situ HybridizationInflammasomeInflammationInflammation MediatorsInflammatoryInflammatory ResponseInterleukin-1Interleukin-18InterventionKnock-outKnockout MiceLeadMediatingMediator of activation proteinMusMuscle CellsMyocarditisNecrosisPhenotypePlayPopulationPreventionProcessRoleSignal TransductionSignaling MoleculeSiteStimulusStressT-LymphocyteTimeTissuesTransgenic MiceTransgenic OrganismsVentricularVentricular DysfunctionWorkcalmodulin-dependent protein kinase IIcardiogenesiscell typechemokinecytokineimmune activationknock-downmacrophagenovelp65pressurepreventrecruitresponsesingle-cell RNA sequencing
项目摘要
ABSTRACT
The heart responds to stress through hypertrophic growth of cardiomyocytes and progresses to heart failure
when stress is sustained. Our previous studies showed that hypertrophy in response to a variety of stimuli
occurs independent of signaling through the calcium/calmodulin dependent protein kinase II (CaMKII) but that
progression to heart failure is attenuated when CaMKII is deleted. Inflammation is a key contributor to the
adverse remodeling associated with heart failure. The long term objective of this proposal is to
demonstrate that CaMKII signaling within cardiomyocytes initiates cardiac inflammation in response to
non-ischemic interventions such as pressure overload (TAC) and that this plays a significant role in
the development of heart failure. Studies proposed in Aim 1 determine if cardiomyocyte localized CaMKII
signaling drives cardiac inflammation using cardiac specific CaMKII knockout mice (CKO) to demonstrate
loss of TAC-induced inflammatory gene expression and inflammasome activation. We determine if these
responses occur specifically in cardiomyocytes by isolation of adult mouse ventricular myocytes from CTL and
CKO mice, and by in situ hybridization and enzymatic assays in tissue sections. CaMKIIC transgenics and
mice with cardiac specific KO of the p65 subunit of NFkB are used to further demonstrate involvement of the
cardiomyocyte in igniting inflammation. Aim 2 asks whether cardiomyocyte CaMKII signaling contributes to
accumulation of inflammatory/immune cells in response to TAC. Work in this aim uses CKO mice to
demonstrate that TAC promotes immune cell responses through cardiomyocyte CaMKII initiated signals.
Studies focus on macrophages and T-cells, using immunohistochemistry and flow cytometry as well as single
cell RNA seq to comprehensively define specific populations of macrophages that accumulate in the heart.
Cardiac specific KOs or knockdown of chemokines/cytokines is used to demonstrate that generation of these
mediators in cardiomyocytes triggers responses of specific immune cell types. Aim 3 determines if blockade
of cardiomyocyte CaMKII-initiated inflammation attenuates adverse remodeling and at what point this
needs to be accomplished. Proposed studies use cardiac specific KO or inhibition of selected inflammatory
mediators to demonstrate that their formation in cardiomyocytes is critical for development of fibrosis and
ventricular dysfunction following TAC. Conditional gene deletion with AAV9 Cre is used to establish the time at
which maximal benefit from CaMKII inhibition is achieved. Our findings should significantly impact future
research since the cardiomyocyte has not previously been considered as a generator of inflammatory signals,
the mechanisms by which inflammatory responses are activated in the absence of “alarmins” has not
heretofore been determined, and the concept that most effective prevention of heart failure development could
be achieved by early cardiomyocyte-targeted anti-inflammatory interventions is novel.
摘要
项目成果
期刊论文数量(14)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Molecular Signaling to Preserve Mitochondrial Integrity against Ischemic Stress in the Heart: Rescue or Remove Mitochondria in Danger.
- DOI:10.3390/cells10123330
- 发表时间:2021-11-27
- 期刊:
- 影响因子:6
- 作者:Yu JD;Miyamoto S
- 通讯作者:Miyamoto S
SiglecF(HI) Marks Late-Stage Neutrophils of the Infarcted Heart: A Single-Cell Transcriptomic Analysis of Neutrophil Diversification.
- DOI:10.1161/jaha.120.019019
- 发表时间:2021-02-16
- 期刊:
- 影响因子:5.4
- 作者:Calcagno DM;Zhang C;Toomu A;Huang K;Ninh VK;Miyamoto S;Aguirre AD;Fu Z;Heller Brown J;King KR
- 通讯作者:King KR
RhoA signaling increases mitophagy and protects cardiomyocytes against ischemia by stabilizing PINK1 protein and recruiting Parkin to mitochondria.
- DOI:10.1038/s41418-022-01032-w
- 发表时间:2022-12
- 期刊:
- 影响因子:12.4
- 作者:Tu, MichelleZ;Tan, Valerie P.;Yu, Justin D.;Tripathi, Raghav;Bigham, Zahna;Barlow, Melissa;Smith, Jeffrey M.;Brown, Joan Heller;Miyamoto, Shigeki
- 通讯作者:Miyamoto, Shigeki
The contribution of the cardiomyocyte to tissue inflammation in cardiomyopathies.
- DOI:10.1016/j.cophys.2020.10.003
- 发表时间:2021-03
- 期刊:
- 影响因子:2.5
- 作者:Ninh VK;Brown JH
- 通讯作者:Brown JH
A Kinase Interacting Protein 1 (AKIP1) promotes cardiomyocyte elongation and physiological cardiac remodelling.
- DOI:10.1038/s41598-023-30514-1
- 发表时间:2023-03-10
- 期刊:
- 影响因子:4.6
- 作者:Nijholt, Kirsten T.;Sanchez-Aguilera, Pablo I.;Booij, Harmen G.;Oberdorf-Maass, Silke U.;Dokter, Martin M.;Wolters, Anouk H. G.;Giepmans, Ben N. G.;van Gilst, Wiek H.;Brown, Joan H.;de Boer, Rudolf A.;Sillje, Herman H. W.;Westenbrink, B. Daan
- 通讯作者:Westenbrink, B. Daan
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JOAN HELLER BROWN其他文献
JOAN HELLER BROWN的其他文献
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{{ truncateString('JOAN HELLER BROWN', 18)}}的其他基金
RhoA and GPCR mediated transcriptional activation regulates glioblastoma
RhoA 和 GPCR 介导的转录激活调节胶质母细胞瘤
- 批准号:
9905280 - 财政年份:2018
- 资助金额:
$ 39.5万 - 项目类别:
RhoA and GPCR mediated transcriptional activation regulates glioblastoma
RhoA 和 GPCR 介导的转录激活调节胶质母细胞瘤
- 批准号:
10356023 - 财政年份:2018
- 资助金额:
$ 39.5万 - 项目类别:
Molecular Mechanism and Therapy for Ocular Melanoma
眼部黑色素瘤的分子机制及治疗
- 批准号:
10341047 - 财政年份:2017
- 资助金额:
$ 39.5万 - 项目类别:
Molecular Mechanism and Therapy for Ocular Melanoma
眼部黑色素瘤的分子机制及治疗
- 批准号:
10018829 - 财政年份:2017
- 资助金额:
$ 39.5万 - 项目类别:
2010 Cardiac Regulatory Mechanisms Gordon Research Conference
2010年心脏调节机制戈登研究会议
- 批准号:
7905509 - 财政年份:2010
- 资助金额:
$ 39.5万 - 项目类别:
Restoration of Myocardial Healing through G-coupled Protein Receptor Signaling
通过 G 偶联蛋白受体信号转导恢复心肌愈合
- 批准号:
8452816 - 财政年份:2006
- 资助金额:
$ 39.5万 - 项目类别:
Restoration of Myocardial Healing through G-coupled Protein Receptor Signaling
通过 G 偶联蛋白受体信号转导恢复心肌愈合
- 批准号:
8734475 - 财政年份:2006
- 资助金额:
$ 39.5万 - 项目类别:
Restoration of Myocardial Healing through G-coupled Protein Receptor Signaling
通过 G 偶联蛋白受体信号传导恢复心肌愈合
- 批准号:
9324068 - 财政年份:2006
- 资助金额:
$ 39.5万 - 项目类别:
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