Regulatroy 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:8818507
- 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 2018-09-30
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAcute myocardial infarctionAffectAfrican AmericanAftercareAlcohol consumptionAnti-Inflammatory AgentsAnti-inflammatoryApolipoprotein EAreaAtherosclerosisAttenuatedBiological PreservationBloodCardiacCause of DeathCessation of lifeChromatin StructureChronicClinical TreatmentComplexCongestiveCongestive Heart FailureCoronary ArteriosclerosisCoronary heart diseaseCytolysisDataDeath RateDevelopmentDiabetes MellitusEFRACEndothelial CellsEnzyme InhibitionEnzymesFibrosisFosteringGene ExpressionGenesGenetic ProgrammingHealedHeartHeart DiseasesHeart failureHistone DeacetylaseHistonesHourHypertensionImpaired wound healingIn VitroInfarctionInflammationInflammatoryInjuryLeadMatrix MetalloproteinasesMediatingMediator of activation proteinModelingMolecularMonocytosisMusMyocardial InfarctionMyocardiumMyofibroblastObesityOverweightPatientsPeptide HydrolasesPhasePhenotypePlayPopulationPre-Clinical ModelProcessRecruitment ActivityRegulationRheumatoid ArthritisRoleSeptic ShockSignal TransductionSmokingStem cellsStimulusTestingTherapeuticTimeTissuesTransferaseTranslatingUnited StatesVentricular FunctionVentricular RemodelingVeteransWomancytokineextracellularhealingheart disease riskin vivoinhibitor/antagonistinsightmacrophagemenmonocytemortalitynanoparticleneutrophilpatient populationpreventpublic health relevancerepairedresponsetargeted deliverytissue regenerationtranscription factortranslational approachtreatment strategy
项目摘要
DESCRIPTION (provided by applicant):
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 progress to congestive heart fail-ure. 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. Recent studies have demonstrated that increasing the M1 to M2 polarization appears to be an attractive strategy for decreasing inflammation and improvement of infarct healing and repair. Our preliminary data provide evidence for the first time that class I HDACs regulate M1 to M2 polarization of macrophages of the post-MI heart. Therefore, we hypothesize that class I HDACs serve as a master regulator of macrophage polarization and HDAC inhibitors reprogram the infiltrating monocytes and resulting macrophages toward the M2 phenotype in the post-MI heart. We have proposed Three Aims to test our hypothesis. Aim 1) Demonstrate that inhibition of class I HDACs attenuates M1 macrophage recruitment and promotes M1 to M2 polarization, which fosters infarct healing. Aim 2) Determine if targeted delivery of a class I HDAC inhibitor to inflammatory monocytes attenuates MI injury. Aim 3) Determine if treatment with a class I selective HDAC inhibitor in a murine model of chronic inflammation commonly seen in patients with atherosclerosis, results in reduced deleterious remodeling and preservation of ventricular function. Our approach will allow us to directly test whether targeted delivery of class I HDAC inhibitors to monocytes and macrophages can override the overwhelming inflammatory extracellular signaling milieu in the acute MI ventricle to reprogram macrophage phenotype to influence M1 to M2 transition. 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.
描述(由申请人提供):
心脏病是男性和女性死亡的主要原因,每年有超过 600,000 人死亡(占死亡率的 25%)。冠心病是最常见的心脏病类型,每年约有 715,000 名患者心脏病发作。我们东南部患者群体的死亡率甚至更高,其中非裔美国人的死亡率更高。我们的 VA 患者反映了当地心脏病风险较高的人群,通常表现为高血压、糖尿病、肥胖或超重、吸烟和过量饮酒。因心肌梗塞 (MI) 导致左心室损伤的 VA 患者会经历心室重塑,这可能导致心室扩张并进展为充血性心力衰竭。单核细胞衍生的巨噬细胞被认为在梗塞愈合的调节中发挥重要作用。 MI 后修复由双相过程组成,其中 I 期由炎症 M1 巨噬细胞介导,这些巨噬细胞具有吞噬能力,并分泌高水平的 MMP 和促炎介质。相比之下,M2 巨噬细胞产生抗炎细胞因子,并与肌成纤维细胞、内皮细胞、实质细胞和局部祖细胞通讯,帮助协调受损组织的重塑和修复。炎症单核细胞和巨噬细胞的受控募集对于正常愈合至关重要,但这些炎症单核细胞和 M1 巨噬细胞的过度或长时间募集会导致有害的重塑和心力衰竭。最近的研究表明,增加 M1 至 M2 极化似乎是减少炎症和改善梗塞愈合和修复的一种有吸引力的策略。我们的初步数据首次提供了 I 类 HDAC 调节 MI 后心脏巨噬细胞 M1 至 M2 极化的证据。因此,我们假设 I 类 HDAC 作为巨噬细胞极化的主要调节剂,并且 HDAC 抑制剂将浸润单核细胞和产生的巨噬细胞重新编程为 MI 后心脏中的 M2 表型。我们提出了三个目标来检验我们的假设。目标 1) 证明抑制 I 类 HDAC 会减弱 M1 巨噬细胞的募集并促进 M1 到 M2 极化,从而促进梗塞愈合。目标 2) 确定向炎性单核细胞靶向递送 I 类 HDAC 抑制剂是否可以减轻 MI 损伤。目标 3) 确定在动脉粥样硬化患者常见的慢性炎症小鼠模型中使用 I 类选择性 HDAC 抑制剂治疗是否会减少有害重塑并保留心室功能。我们的方法将使我们能够直接测试向单核细胞和巨噬细胞靶向递送 I 类 HDAC 抑制剂是否可以克服急性 MI 心室中压倒性的炎症细胞外信号传导环境,从而重新编程巨噬细胞表型,从而影响 M1 到 M2 的转变。重要的是,我们的研究将为我们提供关于 I 类 HDAC 在调节巨噬细胞极化中的作用的重要新分子见解,并可能为治疗 MI 后 VA 患者开辟新的转化方法。希望该应用的研究结果能够转化为新的、成功的临床治疗策略,以改善退伍军人的心肌梗死后损伤。
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
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
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Regulatory Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
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10830235 - 财政年份:2014
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Regulatory Role of HDAC in Post-MI Ventricular Remodeling
HDAC 在 MI 后心室重构中的调节作用
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10455524 - 财政年份:2014
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Regulatroy Role of HDAC in Post-MI Ventricular Remodeling
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