Mechanisms of Myocardial Infarction-induced insulin resistance
心肌梗死引起的胰岛素抵抗的机制
基本信息
- 批准号:10116453
- 负责人:
- 金额:$ 51.63万
- 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:2018-04-01 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:ANXA5 geneAcute myocardial infarctionAddressAdipose tissueAnti-Inflammatory AgentsApoptosisApoptoticApplications GrantsArterial Fatty StreakBone MarrowCause of DeathCellsColony-Stimulating Factor ReceptorsCoronaryDataDeveloped CountriesDiabetes MellitusDietEventExhibitsFlow CytometryGeneticGlucoseGlucose ClampGlucose IntoleranceHigh Fat DietHumanHyperglycemiaImmunofluorescence ImmunologicInflammatoryInsulin ResistanceInterleukin-1Interleukin-1 betaInterleukin-13Interleukin-4Interleukin-6KnowledgeLigationMacrophage Colony-Stimulating FactorMacrophage Colony-Stimulating Factor ReceptorMouse StrainsMusMyelogenousMyeloid CellsMyocardial InfarctionNon-Insulin-Dependent Diabetes MellitusOrganParabiosisPatientsPhenotypePlayProductionPropidium DiiodideRecording of previous eventsReportingRoleSeriesSourceSupplementationTNF geneTamoxifenTestingTissue DifferentiationTissuesVisceralcytokinedrug developmentexperimental studyfasting blood glucose levelimprovedinflammatory milieuinsulin sensitivityintravital microscopymacrophagemonocytemortalitymouse modelneutralizing antibodynovel therapeuticspreventrecruit
项目摘要
Myocardial infarction (MI) is the leading cause of mortality in the USA. Patients develop insulin resistance
after acute MI. In a mouse model of MI, we found coronary ligation significantly increased insulin resistance
in mice fed with either a chow diet or high fat diet. Recent studies have shown that MI-induced insulin
resistance has direct proatherogenic effects at the level of atherosclerotic plaques leading to a series of
cellular atherogenic events and plaque progression. But the mechanistic underpinnings of insulin resistance
after MI are not explored. We have recently shown that MI increases production of inflammatory monocytes,
which can infiltrate visceral adipose tissue (VAT) and differentiate into macrophages. Consistently, our
preliminary data revealed that MI-induced insulin resistance was associated with accumulation of CX3CR1+
CCR2+ monocyte-derived macrophages in VAT. We hypothesize that the influx of monocyte-derived
macrophages into VAT after MI creates an inflammatory milieu, resulting in insulin resistance. We will test
the hypothesis in three specific aims. 1.We will investigate the dynamics of macrophage subsets in VAT
after MI. We will use flow cytometry and intravital microscopy to investigate monocyte accumulation in VAT
after MI. 2.To test the mechanisms of MI-induced insulin resistance, we will investigate if loss of M-CSF
after MI leads to insulin resistance. Our preliminary experiments showed that coronary ligation in mice
reduced systemic levels of M-CSF, a cytokine responsible for tissue resident macrophage survival. 3. We
will investigate if the accumulation of monocyte-derived macrophages induces insulin resistance after MI
using a mouse strain of tamoxifen-inducible CX3CR1. Furthermore, since monocyte-derived VAT
macrophages express high levels of IL-1β, we will use IL-1β neutralizing antibody to explore whether it can
improve insulin sensitivity. The proposed grant application will further our understanding of mechanisms
behind MI-induced insulin resistance and explore new therapeutic avenues.
心肌梗死(MI)是美国死亡的主要原因。患者出现胰岛素抵抗
急性心肌梗死后在小鼠心肌梗死模型中,我们发现冠状动脉结扎显著增加了胰岛素抵抗
在喂食普通饲料或高脂肪饲料的小鼠中。最近的研究表明MI诱导的胰岛素
阻力在动脉粥样硬化斑块水平具有直接的促动脉粥样硬化作用,导致一系列的
细胞致动脉粥样硬化事件和斑块进展。但是胰岛素抵抗的机制基础
在MI未被探索之后。我们最近发现MI增加了炎症单核细胞的产生,
其可渗入内脏脂肪组织(VAT)并分化成巨噬细胞。因此,我们的
初步数据显示MI诱导的胰岛素抵抗与CX 3CR 1+的积聚有关
VAT中的CCR 2+单核细胞衍生的巨噬细胞。我们假设单核细胞源性
MI后巨噬细胞转化为VAT产生炎症环境,导致胰岛素抵抗。我们将测试
三个具体目标的假设。1.研究巨噬细胞亚群在VAT中的动态变化
MI后。我们将使用流式细胞术和活体显微镜来研究VAT中单核细胞的积聚,
MI后。2.为了探讨MI诱导的胰岛素抵抗的机制,我们将研究M-CSF的丢失是否与MI的胰岛素抵抗有关。
导致胰岛素抵抗。我们的初步实验表明,小鼠冠状动脉结扎
降低全身M-CSF水平,M-CSF是一种负责组织驻留巨噬细胞存活的细胞因子。3.我们
将研究MI后单核细胞源性巨噬细胞的积聚是否诱导胰岛素抵抗
使用他莫昔芬诱导型CX 3CR 1小鼠品系。此外,由于单一来源的增值税
巨噬细胞表达高水平的IL-1β,我们将使用IL-1β中和抗体来探索它是否可以
改善胰岛素敏感性。拟议的赠款申请将进一步加深我们对机制的理解
背后MI诱导的胰岛素抵抗和探索新的治疗途径。
项目成果
期刊论文数量(0)
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{{ truncateString('Partha Dutta', 18)}}的其他基金
The role of SerpinB2 in insulin resistance and inflammation
SerpinB2 在胰岛素抵抗和炎症中的作用
- 批准号:
10445110 - 财政年份:2022
- 资助金额:
$ 51.63万 - 项目类别:
The role of SerpinB2 in insulin resistance and inflammation
SerpinB2 在胰岛素抵抗和炎症中的作用
- 批准号:
10615780 - 财政年份:2022
- 资助金额:
$ 51.63万 - 项目类别:
Mechanisms of myelopoiesis after myocardial infarction
心肌梗死后骨髓生成机制
- 批准号:
10415059 - 财政年份:2020
- 资助金额:
$ 51.63万 - 项目类别:
The role of microglia Nek6 in myocardial infarction-induced cognitive impairment
小胶质细胞 Nek6 在心肌梗死所致认知障碍中的作用
- 批准号:
10713921 - 财政年份:2020
- 资助金额:
$ 51.63万 - 项目类别:
Mechanisms of myelopoiesis after myocardial infarction
心肌梗死后骨髓生成机制
- 批准号:
10625852 - 财政年份:2020
- 资助金额:
$ 51.63万 - 项目类别:
Mechanisms of myelopoiesis after myocardial infarction
心肌梗死后骨髓生成机制
- 批准号:
10171888 - 财政年份:2020
- 资助金额:
$ 51.63万 - 项目类别:
Effect of diabetes on myelopoiesis and atherosclerosis
糖尿病对骨髓细胞生成和动脉粥样硬化的影响
- 批准号:
9172344 - 财政年份:2013
- 资助金额:
$ 51.63万 - 项目类别:
Effect of diabetes on myelopoiesis and atherosclerosis
糖尿病对骨髓细胞生成和动脉粥样硬化的影响
- 批准号:
8617386 - 财政年份:2013
- 资助金额:
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