Project 1:Diabetes, RAGE/DIAPH1 and Myocardial Infarction
项目1:糖尿病、RAGE/DIAPH1与心肌梗死
基本信息
- 批准号:10407557
- 负责人:
- 金额:$ 56.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAttenuatedBindingBioinformaticsBone MarrowCalciumCardiacCardiac MyocytesCardiovascular DiseasesCell CommunicationCell DeathCell Death Signaling ProcessCellsCollaborationsCytoplasmic TailDataDiabetes MellitusEndothelial CellsEnergy MetabolismFluorescenceFoundationsGenetic TranscriptionGlucoseGoalsGuanosine Triphosphate PhosphohydrolasesHeartHyperglycemiaInfarctionInflammationInjuryIschemiaKnockout MiceLigandsLoxP-flanked alleleMagnetic Resonance SpectroscopyMass Spectrum AnalysisMeasurementMediatingMetabolicMetabolic dysfunctionMitochondriaMolecularMonitorMorbidity - disease rateMusMyocardial InfarctionMyocardial IschemiaMyocardiumOxidative StressPatientsPlayProcessProteomicsPublishingRAGE geneRecoveryRecovery of FunctionRegulationReperfusion InjuryReperfusion TherapyRoleSarcoplasmic ReticulumSignal TransductionStressTechniquesTestingTherapeuticTherapeutic InterventionTissuesTransplantationWild Type MouseWorkantagonistcell motilitydiabeticheart cellimprovedin vivoin vivo Modelischemic injurylimb ischemiamacrophagemonocytemortalitymouse modelmutantmyocardial injurynovelpreservationprogramsreceptor for advanced glycation endproductsrecruitrepairedsmall moleculetranscriptomics
项目摘要
Project Summary: Project 1
Cardiovascular disease (CVD), that include increased sensitivity of diabetic (DM) myocardium to ischemic injury,
represents the major cause of morbidity and mortality in patients with diabetes. We have uncovered key roles
for the receptor for advanced glycation end products (RAGE -gene symbol Ager) in DM and myocardial
ischemia/reperfusion (I/R), as global deletion of Ager attenuated myocardial injury, reduced oxidative stress,
increased functional recovery and preservation of ATP compared to wild-type (WT) littermates. Mechanisms by
which Ager deletion confers metabolic and functional protection in DM and non-DM (NDM) I/R hearts will
be the focus of this project. Our program discovered that the RAGE cytoplasmic domain interacts with
diaphanous-1 (DIAPH1), an effector of RhoGTPases, is essential for RAGE ligand-mediated cellular migration
and activation of cdc42/rac-1. Our recent studies demonstrated that DIAPH1 is expressed in cardiomyocytes
(CMs) and that I/R increases expression of Diaph1. Key preliminary data reveal reduced infarct size and
improved functional recovery after I/R in (a) WT mice transplanted with bone marrow derived cells from Ager null
mice,(b) mice with CM specific deletion of Ager/Diaph1, and (c) WT mice hearts perfused with conditioned media
from Ager null or Diaph1 null macrophages (MΦs). Novel findings in CMs and MΦs reveal that DIAPH1 interacts
with mitochondrial GTPase mitofusin2 (MFN2) and augments MFN2's tethering of sarcoplasmic reticulum (SR)
to mitochondria (mito) and consequently mito calcium regulation. Importantly, our data shows that high glucose,
ligands of RAGE, and RAGE-DIAPH1 interaction further augments DIAPH1-MFN2 driven mito-SR tethering.
Taken together, these data led us to hypothesize that RAGE/DIAPH1 mediates DIAPH1-MFN2 driven Mito-
SR interactions, altered calcium regulation, cell death signaling and metabolic dysfunction in I/R hearts
by cell intrinsic mechanisms in MΦs, and via MΦ-CM cross-talk. We will probe comprehensive mechanisms
in cardiac stresses evoked by I/R using murine models, both in the absence and presence of DM. We will employ
novel Ager and Diaph1 floxed mice, small molecule antagonists of RAGE-DIAPH1 interaction, state-of-the-art
molecular techniques, proteomics, and magnetic resonance spectroscopy to uncover mechanisms of I/R injury
in DM hearts.Proposed studies in this project will identify novel mechanism MΦ specific mechanism, as well as
MΦ-CM cross talk mechanisms by which RAGE-DIAPH1 modulates I/R injury in hearts, particularly in DM hearts.
Identification of these mechanisms, along with testing of novel small molecules that block RAGE/DIAPH1
interaction, will pave the way for therapeutic interventions to protect DM hearts from I/R injury. Project 1 will
work closely with Projects 2 and 3 and the two Cores to achieve these goals.
项目摘要:项目1
心血管疾病(CVD),包括对缺血性损伤的糖尿病(DM)心肌的敏感性提高,
代表了糖尿病患者发病率和死亡率的主要原因。我们发现了关键角色
用于DM和心肌的高级糖基化终端产品的受体
缺血/再灌注(I/R),随着全球衰减AGER减弱心肌损伤,氧化应激减少,
与野生型(WT)同窝仔相比,ATP的功能恢复和保存增加。机制
哪些AGER删除在DM和非DM(NDM)I/R HEARTS中供应代谢和功能保护
成为该项目的重点。我们的程序发现愤怒的细胞质结构域与
diaphanous-1(Diaph1)是Rhogtpases的效应子,对于愤怒配体介导的细胞迁移至关重要
和CDC42/RAC-1的激活。我们最近的研究表明,在心肌细胞中表达diaph1
(CMS)并且I/R增加了diaph1的表达。关键初步数据显示,基础架构的大小和
I/R在(A)WT小鼠中用骨髓衍生的细胞移植的(A)WT小鼠的功能恢复得到改善
小鼠,(b)具有cm特异性衰减的小鼠,ager/diaph1,(c)wt小鼠心脏用条件培养基灌注
来自Ager Null或Diaph1 Null巨噬细胞(MφS)。 CMS和MφS中的新发现表明,Diaph1相互作用
用线粒体GTPase Mitofusin2(MFN2)和增强MFN2的肌浆网的束缚(SR)
到线粒体(MITO),并因此是线粒体调节。重要的是,我们的数据表明高葡萄糖,
愤怒的配体和rage-diaph1相互作用进一步增强了diaph1-mfn2驱动的Mito-SR束缚。
综上所述,这些数据导致我们假设Rage/Diaph1介导Diaph1-Mfn2驱动的Mito-
I/R心脏中的SR相互作用,钙调节改变,细胞死亡信号传导和代谢功能障碍
通过Mφs中的细胞固有机制,并通过Mφ-CM串扰。我们将探测全面的机制
在不存在和存在DM的情况下,I/R诱发的心脏应力中。我们将雇用
新型Ager和Diaph1 Floxed小鼠,rage-Diaph1相互作用的小分子拮抗剂,最新的
分子技术,蛋白质组学和磁共振光谱,以发现I/R损伤的机制
在DM心脏中。该项目中的研究将确定新机制Mφ特定机制以及
mφ-cm串扰机制通过rage-diaph1调节心脏中的I/r损伤,尤其是在DM心脏中。
这些机制的识别,以及对阻断愤怒/diaph1的新型小分子的测试
相互作用,将为治疗干预措施铺平道路,以保护DM心脏免受I/R伤害。项目1将
与项目2和3和两个核心紧密合作以实现这些目标。
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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Ravichandran Ramasamy其他文献
Ravichandran Ramasamy的其他文献
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{{ truncateString('Ravichandran Ramasamy', 18)}}的其他基金
Targeting RAGE/DIAPH1: Novel Therapeutic Strategy for Diabetic Complications
靶向 RAGE/DIAPH1:糖尿病并发症的新治疗策略
- 批准号:
10197120 - 财政年份:2020
- 资助金额:
$ 56.07万 - 项目类别:
Targeting RAGE/DIAPH1: Novel Therapeutic Strategy for Diabetic Complications
靶向 RAGE/DIAPH1:糖尿病并发症的新治疗策略
- 批准号:
10368080 - 财政年份:2020
- 资助金额:
$ 56.07万 - 项目类别:
Targeting RAGE/DIAPH1: Novel Therapeutic Strategy for Diabetic Complications
靶向 RAGE/DIAPH1:糖尿病并发症的新治疗策略
- 批准号:
10596466 - 财政年份:2020
- 资助金额:
$ 56.07万 - 项目类别:
Targeting RAGE/DIAPH1: Novel Therapeutic Strategy for Diabetic Complications
靶向 RAGE/DIAPH1:糖尿病并发症的新治疗策略
- 批准号:
10055037 - 财政年份:2020
- 资助金额:
$ 56.07万 - 项目类别:
Project 1:Diabetes, RAGE/DIAPH1 and Myocardial Infarction
项目1:糖尿病、RAGE/DIAPH1与心肌梗死
- 批准号:
10191021 - 财政年份:2019
- 资助金额:
$ 56.07万 - 项目类别:
Core 2: Mouse, Cell and Protein Support, Data Management and Biostatistics Core
核心 2:小鼠、细胞和蛋白质支持、数据管理和生物统计学核心
- 批准号:
10191020 - 财政年份:2019
- 资助金额:
$ 56.07万 - 项目类别:
Core 2: Mouse, Cell and Protein Support, Data Management and Biostatistics Core
核心 2:小鼠、细胞和蛋白质支持、数据管理和生物统计学核心
- 批准号:
10642706 - 财政年份:2019
- 资助金额:
$ 56.07万 - 项目类别:
Core 2: Mouse, Cell and Protein Support, Data Management and Biostatistics Core
核心 2:小鼠、细胞和蛋白质支持、数据管理和生物统计学核心
- 批准号:
10407556 - 财政年份:2019
- 资助金额:
$ 56.07万 - 项目类别:
Project 1:Diabetes, RAGE/DIAPH1 and Myocardial Infarction
项目1:糖尿病、RAGE/DIAPH1与心肌梗塞
- 批准号:
10642708 - 财政年份:2019
- 资助金额:
$ 56.07万 - 项目类别:
RAGE/mDia1, Macrophage Trafficking and Inflammation in High Fat Feeding
RAGE/mDia1、高脂肪喂养中的巨噬细胞运输和炎症
- 批准号:
9906204 - 财政年份:2016
- 资助金额:
$ 56.07万 - 项目类别:
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