Regulatory Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
基本信息
- 批准号:10265359
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-10-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAffectAfrican AmericanAlcohol consumptionAnti-Inflammatory AgentsAppearanceAreaBackCD86 geneCardiacCause of DeathCellsCessation of lifeChromatin StructureCicatrixClinical TreatmentComplexCongestive Heart FailureCoronary heart diseaseDataDeath RateDiabetes MellitusEFRACEndothelial CellsEnvironmentEnzyme InhibitionEnzymesEquilibriumExcisionExtracellular MatrixFibroblastsFibrosisFosteringGene ExpressionGene Expression ProfilingGenetic TranscriptionGlycopeptidesHeartHeart DiseasesHeart failureHeterogeneityHistone DeacetylaseHistone Deacetylase InhibitorHistonesHourHypertensionImageInfarctionInflammationInflammatoryInjuryInterleukin-10Interleukin-4KineticsLeadLipidsMapsMass Spectrum AnalysisMatrix MetalloproteinasesMediatingMediator of activation proteinModelingMolecularMyocardial InfarctionMyocardial IschemiaMyocardiumMyofibroblastObesityOverweightPatientsPeptide HydrolasesPeptidesPhagocytesPhagocytosisPhasePhenotypePlayPolysaccharidesPopulationPopulation HeterogeneityPre-Clinical ModelProcessProteolysisRegulationResolutionReverse Transcriptase Polymerase Chain ReactionRoleSmokingSpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationTestingTherapeuticTissuesTransferaseTranslatingUnited StatesVentricular FunctionVentricular RemodelingVeteransWomanWorkcytokineepigenetic regulationhealingheart damageheart disease riskimprovedinjuredinsightischemic injurymacrophagemenmonocytemortalitynanoparticlenecrotic tissueneovascularizationneutrophilpatient populationpreservationrecruitrepairedresponsestem cellstargeted deliverytissue regenerationtranscription factortranscriptometranslational approachtreatment strategy
项目摘要
Heart disease is the leading cause of death for both men and women with over 600,000 deaths/year
(25% of mortality). Coronary heart disease is the most common type of heart disease with about
715,000 patients suffering a heart attack each year. Death rates in our patient population in the
southeast are even higher with African Americans having higher rates yet. Our VA patients reflect our
local population with elevated risk of heart disease often presenting with hypertension, diabetes,
obesity or overweight, smoking and excessive alcohol use. VA patients who have incurred LV injury
due to myocardial infarction (MI) undergo ventricular remodeling, which can lead to chamber dilation
and progression to congestive heart failure. Monocyte-derived macrophages are believed to play a
major role in the regulation of infarct healing. Post-MI repair is made up of a biphasic process with
phase I mediated by inflammatory M1 macrophages that are phagocytic, and secrete high levels of
MMPs and proinflammatory mediators. By contrast the M2 macrophages produce anti-inflammatory
cytokines and communicate with myofibroblasts, endothelial cells, parenchymal and local progenitor
cells to help coordinate remodeling and repair of the damaged tissue. The controlled recruitment of the
inflammatory monocytes and resulting macrophages is essential for proper healing, but excessive or
prolonged recruitment of these inflammatory monocytes and M1 macrophage results in deleterious
remodeling and heart failure. Histone deacetylases (HDACs) and histone acetyl-transferases (HATs)
are critical players in regulating gene expression via modulation of chromatin structure and the
acetylation of transcription factors. We and others have demonstrated that HDAC inhibition is
efficacious in pre-clinical models of ischemic heart disease. Our data show HDAC inhibition in a model
of MI results in the dramatic increase in the recruitment of reparative macrophages by 1 d post-MI
which correlates with significantly lower LV dilation and preserves LV ejection fraction. Therefore, we
hypothesize that HDACs serve as a master regulator of macrophage polarization, promoting
resolution of inflammation and protection of adverse remodeling through secretion of pro-
reparative factors. By bringing the HDAC activity in the injured myocardium back into balance, we
change the kinetics of appearance of reparative macrophages via epigenetic regulation of
macrophages and favorably influence the complex cross-talk between macrophages and neutrophils
and macrophages and fibroblasts. We have 3 Aims to test our hypothesis. Aim 1 Determine how HDAC
inhibition in the post MI ventricle affects macrophage phenotype, function and resulting tissue
microenvironment in order to foster infarct healing. Aim 2 Determine how nanoparticle targeted delivery
of HDAC inhibition to monocytes and macrophages affects the post-MI macrophage transcriptome,
function and resulting tissue microenvironment. Aim 3 Determine how nanoparticle targeted delivery of
HDAC inhibition to monocytes and macrophages affects the post-MI macrophage-cross talk with
neutrophils and fibroblasts. Importantly, our study will give us important new molecular insights into the
role of class I HDACs in regulating macrophage polarization and possibly open a new translational
approach for treatment of post-MI VA patients. It is hoped that the findings of this application will be
translated into new and successful clinical treatment strategies to ameliorate post-MI injury for our
Veterans.
心脏病是男女死亡的主要原因,每年有60多万人死亡
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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Donald R. Menick其他文献
Two Groups Control Light-Induced Schiff Base Deprotonation and the Proton Affinity of Asp<sup>85</sup> in the Arg<sup>82</sup>His Mutant of Bacteriorhodopsin
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1999-11-01 - 期刊:
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Eleonora S. Imasheva;Sergei P. Balashov;Thomas G. Ebrey;Ning Chen;Rosalie K. Crouch;Donald R. Menick - 通讯作者:
Donald R. Menick
Role of p38/Akt Signaling Pathway in the Regulation of Sodium/Calcium Exchanger Expression in Adult Cardiomyocytes
- DOI:
10.1016/j.cardfail.2010.06.077 - 发表时间:
2010-08-01 - 期刊:
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Donald R. Menick
Cloning of Cardiac, Kidney, and Brain Promoters of the Feline <em>ncx1</em> Gene
- DOI:
10.1074/jbc.272.17.11510 - 发表时间:
1997-04-25 - 期刊:
- 影响因子:
- 作者:
Kimberly V. Barnes;Guangmao Cheng;Myra M. Dawson;Donald R. Menick - 通讯作者:
Donald R. Menick
Role of Nkx2.5 Acetylation by Histone Deacetylases in Regulating Sodium/Calcium Exchanger Expression in Adult Cardiomyocytes
- DOI:
10.1016/j.cardfail.2010.06.140 - 发表时间:
2010-08-01 - 期刊:
- 影响因子:
- 作者:
Mona S. Li;Santhosh K. Mani;Benjamin Addy;Thirumagal Thiagarajan;Christine B. Kern;Donald R. Menick - 通讯作者:
Donald R. Menick
Donald R. Menick的其他文献
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{{ truncateString('Donald R. Menick', 18)}}的其他基金
ShEEP application for Integrated Hypoxia Exposure and Analysis Core
用于集成缺氧暴露和分析核心的 ShEEP 应用
- 批准号:
9795680 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Regulatory Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
- 批准号:
9919999 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Regulatroy Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
- 批准号:
8818507 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Regulatory Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
- 批准号:
10830235 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Regulatory Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
- 批准号:
10455524 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Regulatroy Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
- 批准号:
8975085 - 财政年份:2014
- 资助金额:
-- - 项目类别:
MAP4 REGULATION OF CARDIAC MICROTUBULE NETWORK DENSITY
MAP4 心脏微管网络密度的调节
- 批准号:
8639216 - 财政年份:2010
- 资助金额:
-- - 项目类别:
MAP4 REGULATION OF CARDIAC MICROTUBULE NETWORK DENSITY
MAP4 心脏微管网络密度的调节
- 批准号:
8235944 - 财政年份:2010
- 资助金额:
-- - 项目类别:
MAP4 REGULATION OF CARDIAC MICROTUBULE NETWORK DENSITY
MAP4 心脏微管网络密度的调节
- 批准号:
8490586 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Research Education Program for Minority Medical Students
少数民族医学生研究教育计划
- 批准号:
8829317 - 财政年份:2009
- 资助金额:
-- - 项目类别:
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