Cardiac Macrophages as Disease Drivers in Chronic Ischemic Heart Failure
心脏巨噬细胞作为慢性缺血性心力衰竭的疾病驱动因素
基本信息
- 批准号:10613345
- 负责人:
- 金额:$ 52.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:Adoptive Cell TransfersAdoptive TransferAntibodiesAntisense OligonucleotidesAttenuatedBehaviorBiological AssayBiological Response ModifiersBone MarrowC57BL/6 MouseCardiacCell ProliferationCell SeparationCellsCellular Indexing of Transcriptomes and Epitopes by SequencingCharacteristicsChronicClassificationClinicalCongestive Heart FailureCoronaryDataDevelopmentDiseaseDisease ProgressionDisease modelExhibitsFemaleFibrosisFlow CytometryFunctional disorderGenesGeneticGenetic TranscriptionHeartHeart InjuriesHeart failureHumanImmuneImmunohistochemistryInflammationInflammatoryInjectionsInterleukin 4 ReceptorInterleukin-10Interleukin-13Interleukin-4IschemiaKnockout MiceLate EffectsLeft Ventricular RemodelingLigationLinkMacrophageMeasuresMediatorModelingMusMyelogenousMyocardial InfarctionMyocardial IschemiaMyocarditisMyocardiumMyofibroblastPTPRC genePathogenesisPathologicPathway interactionsPhagocytesPhagocytosisPopulationPrognosisProgressive DiseaseProliferatingProteinsRoleSignal PathwaySignal TransductionSortingSpatial DistributionTamoxifenTestingTherapeuticTissue ExpansionTissuesbeta-Chemokinescell typechemokinechemokine receptorcytokinegamma-Chemokinesheart cellimmune activationimmunomodulatory strategyimmunoregulationin vivoinnovationinsightischemic cardiomyopathykinase inhibitormalemonocyteneutralizing antibodynovelnovel strategiesrecruitrepairedself renewing cellself-renewalsingle-cell RNA sequencingsmall moleculesource localizationtargeted treatmenttherapeutic targettissue injurytranscriptomicsvirtual
项目摘要
Macrophage expansion in the failing heart induces tissue injury and is thought to contribute to the progression
of heart failure (HF). The main contributors to macrophage expansion in the failing heart are cells that self-renew
and proliferate independent of the blood monocyte pool (and hence are C-C chemokine receptor 2 [CCR2]–).
However, the role of such locally-sourced macrophages in the pathogenesis of chronic left ventricular (LV)
remodeling is poorly understood. The normal heart harbors macrophages expressing CD206 (Mrc1), along with
the gene markers Ym1, Fizz1, and Arg1, that are primarily CCR2–. These CD206+ macrophages can be activated
by Th2 cytokines such as interleukin(IL)-4/IL-13. Moreover, secreted FIZZ1 contributes to myofibroblast
activation and fibrosis in other disease models. Our pilot data indicate that CD206+ macrophages expressing IL-
4 receptora (IL-4Ra) robustly increase in the failing heart, and suggest that macrophage IL-4/IL-4Ra signaling
promotes LV remodeling and fibrosis, in part through FIZZ1. Hence, we hypothesize that cardiac CD206+
macrophages expressing IL-4Ra and Fizz1 are innate immune mediators of adverse LV remodeling in chronic
HF, and key targets for therapeutic immunomodulation. Three Aims will test this hypothesis. In Aim 1, in a murine
coronary ligation model, using flow cytometry, cell sorting, single cell RNA sequencing (scRNAseq), and
immunohistochemistry, we will comprehensively define pathological alterations in cardiac CD206+ macrophages
in HF, including IL-4Ra levels and downstream signaling, FIZZ1 expression, and in vivo cell abundance,
proliferation, turnover and phagocytic capacity. Using scRNAseq, we will define novel functional subpopulations
of CD206+ macrophages at the transcriptional level in both murine and human failing hearts. In Aim 2, we will
establish the pathogenetic role of CD206+IL-4Ra+ macrophages in HF using CD45.2 inducible myeloid-specific
IL-4Ra knockout mice, deleting myeloid IL-4Ra during chronic HF, and assessing the late effects on LV
remodeling, inflammation, and fibrosis. To establish sufficiency of failing heart CD206+IL-4Ra+ macrophages to
induce tissue injury, we will adoptively transfer sorted cardiac CD206+ macrophages with intact or deleted IL-
4Ra from HF mice into naïve CD45.1 mice via intramyocardial injection and assess LV remodeling 6 w later. To
assess the role of FIZZ1, we will similarly transfer M[IL-4] polarized bone marrow macrophages from wild-type
and Fizz1-/- mice. In Aim 3, we will test potentially translatable therapies to antagonize CD206+IL-4Ra+
macrophages and alleviate chronic LV remodeling, including systemic anti-sense oligonucleotides against IL-
4Ra and Fizz1, anti-IL-4 neutralizing antibody, and GW2580, a small molecule cFMS kinase inhibitor. We will
measure the effects of these therapies on LV remodeling, cardiac macrophages, fibrosis, and chemokine/
cytokine expression. These studies will further our understanding of the innate immune basis for cardiac
inflammation in ischemic HF, provide novel insights into macrophage IL-4-dependent signaling and Fizz1 in the
pathogenesis of LV remodeling, and identify new approaches for cell type-specific immunomodulation in HF.
衰竭心脏中巨噬细胞的扩张导致组织损伤,并被认为是导致进展的原因之一。
心力衰竭(HF)。衰竭心脏中巨噬细胞扩张的主要因素是自我更新的细胞。
并且不依赖于血液单核细胞池而增殖(因此是C-C趋化因子受体2[CCR2]-)。
然而,这种局部来源的巨噬细胞在慢性左心室(LV)发病机制中的作用
人们对重塑知之甚少。正常心脏有巨噬细胞表达CD206(Mrc1),以及
基因标记YM1、Fizz1和Arg1,主要是CCR2-。这些CD206+巨噬细胞可以被激活
Th2细胞因子,如白介素4/白介素13。此外,分泌的FIZZ1对肌成纤维细胞有贡献
在其他疾病模型中的激活和纤维化。我们的实验数据表明,CD206+巨噬细胞表达IL-
4受体(IL-4ra)在心力衰竭时显著升高,提示巨噬细胞IL-4/IL-4ra信号转导
促进左室重构和纤维化,部分是通过FIZZ1。因此,我们假设心脏CD206+
表达IL-4ra和Fizz1的巨噬细胞是慢性左心室不良重构的先天免疫介质
HF和治疗性免疫调节的关键靶点。三个目标将检验这一假设。在目标1中,在小鼠身上
冠状动脉结扎模型,使用流式细胞术、细胞分类、单细胞RNA测序(ScRNAseq)以及
免疫组织化学,我们将全面定义心脏CD206+巨噬细胞的病理变化
在HF中,包括IL-4ra水平和下游信号转导,FIZZ1表达,以及体内细胞丰度,
增殖、周转和吞噬能力。使用scRNAseq,我们将定义新的功能亚群
小鼠和人类衰竭心脏中CD206+巨噬细胞的转录水平。在目标2中,我们将
CD45.2诱导的髓系特异性CD206+IL-4ra+巨噬细胞在心衰发病中的作用
IL-4Ra基因敲除小鼠,慢性心力衰竭时髓系IL-4Ra的缺失及对LV的远期影响
重塑、炎症和纤维化。建立衰竭心脏CD206+IL-4ra+巨噬细胞的充分性
诱导组织损伤,我们将过继转移分选的心脏CD206+巨噬细胞与完整或缺失的IL-
4Ra从心衰小鼠心肌内注入幼稚CD45.1小鼠,6周后评价左室重构。至
评估FIZZ1的作用,我们将类似地将M[IL-4]极化的骨髓巨噬细胞从野生型
和Fizz1-/-老鼠。在目标3中,我们将测试潜在的可翻译疗法来拮抗CD206+IL-4ra+
巨噬细胞和减轻慢性左室重构,包括针对IL-1的系统反义寡核苷酸。
4Ra和Fizz1,抗IL-4中和抗体,小分子cFMS激酶抑制剂GW2580。我们会
测量这些疗法对左室重构、心脏巨噬细胞、纤维化和趋化因子的影响。
细胞因子的表达。这些研究将进一步加深我们对心脏先天性免疫基础的理解。
缺血性心力衰竭的炎症,提供了对巨噬细胞IL-4依赖的信号转导和Fizz1在
研究左室重构的发病机制,为心衰的细胞类型特异性免疫调节寻找新的途径。
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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Sumanth D Prabhu其他文献
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{{ truncateString('Sumanth D Prabhu', 18)}}的其他基金
Cardiac Macrophages as Disease Drivers in Chronic Ischemic Heart Failure
心脏巨噬细胞作为慢性缺血性心力衰竭的疾病驱动因素
- 批准号:
10228245 - 财政年份:2021
- 资助金额:
$ 52.12万 - 项目类别:
Cardiac Macrophages as Disease Drivers in Chronic Ischemic Heart Failure
心脏巨噬细胞作为慢性缺血性心力衰竭的疾病驱动因素
- 批准号:
10592811 - 财政年份:2021
- 资助金额:
$ 52.12万 - 项目类别:
Macrophage Circadian Clock Disruption and Inflammation in Heart Failure
心力衰竭中的巨噬细胞生物钟破坏和炎症
- 批准号:
9901568 - 财政年份:2019
- 资助金额:
$ 52.12万 - 项目类别:
Macrophage Circadian Clock Disruption and Inflammation in Heart Failure
心力衰竭中的巨噬细胞生物钟破坏和炎症
- 批准号:
10597351 - 财政年份:2019
- 资助金额:
$ 52.12万 - 项目类别:
Macrophage Circadian Clock Disruption and Inflammation in Heart Failure
心力衰竭中的巨噬细胞生物钟破坏和炎症
- 批准号:
9764124 - 财政年份:2019
- 资助金额:
$ 52.12万 - 项目类别:
Basic and Translational Science in Heart Failure
心力衰竭的基础和转化科学
- 批准号:
9924622 - 财政年份:2017
- 资助金额:
$ 52.12万 - 项目类别:
6th Annual Comprehensive Cardiovascular Center (CCVC) Symposium: Focus on Cardiovascular Electrophysiology
第六届综合心血管中心(CCVC)年度研讨会:聚焦心血管电生理学
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9397864 - 财政年份:2017
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$ 52.12万 - 项目类别:
Role of Regulatory T-Lymphocytes in Chronic Heart Failure
调节性 T 淋巴细胞在慢性心力衰竭中的作用
- 批准号:
9111666 - 财政年份:2015
- 资助金额:
$ 52.12万 - 项目类别:
Splenic Marginal Zone Macrophages in Chronic Ischemic Heart Failure
慢性缺血性心力衰竭中的脾边缘区巨噬细胞
- 批准号:
9211359 - 财政年份:2015
- 资助金额:
$ 52.12万 - 项目类别:
Role of Regulatory T-Lymphocytes in Chronic Heart Failure
调节性 T 淋巴细胞在慢性心力衰竭中的作用
- 批准号:
8922490 - 财政年份:2015
- 资助金额:
$ 52.12万 - 项目类别:
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