Interfering with the macrophage life cycle of atherosclerosis
干扰动脉粥样硬化的巨噬细胞生命周期
基本信息
- 批准号:9412185
- 负责人:
- 金额:$ 47.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-01-09 至 2020-12-31
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAcuteAnti-inflammatoryApolipoprotein EArterial Fatty StreakAtherosclerosisBiologicalBirthBlood CirculationBone MarrowBone Marrow Stem CellCell Adhesion MoleculesCell MaturationCell ProliferationCellsChemical EngineeringCholesterolClinicClinicalComplicationConsensusDataDisease ProgressionDrug KineticsEncapsulatedEndothelial CellsEnvironmentExcisionExtravasationFoam CellsFormulationGenesGoalsHarvestHematopoieticHematopoietic stem cellsHost DefenseImageImmuneImmunologyInflammationInflammatoryInjectionsIntercellular adhesion molecule 1Interdisciplinary StudyLeukocytesLifeLife Cycle StagesMacrophage Colony-Stimulating Factor ReceptorMeasuresMetabolic syndromeMusMyelogenousMyeloid CellsMyelopoiesisMyocardial InfarctionNanotechnologyObese MiceP-SelectinPatientsPeptide HydrolasesPeripheralPeritonitisPhenotypePneumoniaPrecision therapeuticsPrimatesProcessProductionProliferatingProteinsRNA InterferenceRNA SequencesReactive Oxygen SpeciesRecurrenceResearch PersonnelResolutionRiskSafetySecondary PreventionSignal TransductionSmall Interfering RNAStem cellsStrokeTestingTherapeuticTherapeutic InterventionTherapeutic UsesTissuesTranslatingVascular Cell Adhesion Molecule-1atherogenesischemokinechemokine receptordesigndrug candidatehigh riskimmune functionimprovedin vivoinnovationinsightknock-downmacrophagemigrationmonocytenanomaterialsnanoparticlenanoparticle deliverynovelnovel therapeuticsoxidized low density lipoproteinplaque lesionprogenitorprogramsrecruitrepairedstandard of carestem cell nichetissue repairtranscription factortranscriptome
项目摘要
The problem. The last decade has seen unprecedented progress in understanding the immune processes that
drive atherosclerotic lesion initiation, maturation and complication. In particular, macrophages emerged as key
cells that promote disease progression. If the number of inflammatory macrophages in plaque increases,
atherosclerosis advances towards life-threatening complications. Plaque macrophages derive from circulating
monocytes, which in turn arise from myeloid progenitors and hematopoietic stem cells. When released into
circulation, monocytes follow chemokine gradients towards atherosclerotic plaque, where endothelial adhesion
molecules aid their extravasation into the vessel wall. Once in plaque, inflammatory macrophages destabilize
matrix via proteases and may die locally. Alternatively, if the local environment permits, macrophages may
obtain less inflammatory phenotypes promoting cholesterol removal and tissue repair. These insights have
been difficult to translate into clinically useful therapeutics, partly because broad anti-inflammatory therapy may
compromise beneficial functions of immune cells and host defense. The goal. In this application, we aim to
create a new class of macrophage-targeted atherosclerosis therapeutics using in vivo RNA interference
(RNAi). We will design small interfering RNA (siRNA) targeting discrete proteins which are key decision nodes
for macrophages' fate. We propose to interfere with the life cycle of macrophages with the goal to support
inflammation resolution in atherosclerotic plaque. We will test the central hypothesis that RNAi can be
harnessed to design precision therapeutics for inflammatory atherosclerosis. We will test this hypothesis by
targeting proteins that are essential for macrophage birth (silencing transcription factors MTG16 and PU.1 that
influence activity of hematopoietic stem cells and endothelial targets in the hematopoietic niche), migration
(silencing chemokine receptors in monocytes and adhesion molecules in endothelial cells), maturation
(silencing the M-CSF receptor essential for differentiation of monocytes into macrophages) and polarization
(silencing the essential transcription factor IRF5 that gives rise to M1 macrophages with inflammatory
functions). Innovation. We will use new nanomaterials for delivery to myeloid, progenitor and endothelial cells,
newly and yet-to-be identified siRNA sequences, and target innovative biological targets important in the
macrophage life cycle. Impact. We will develop new therapeutics to dampen inflammatory macrophage activity
in the arterial wall. We will identify a winning therapeutic strategy in mice with post-MI acceleration of
atherosclerosis, a scenario that simulates the vulnerable patient in need of aggressive therapeutic intervention.
Our ultimate goal is to bring these materials into the clinic, improving the currently insufficient standard of care
by enabling better secondary prevention of myocardial infarction and stroke.
这就是问题所在。在过去的十年里,在理解免疫过程方面取得了前所未有的进步
推动动脉粥样硬化病变的发生、成熟和并发症。特别是,巨噬细胞成为关键
促进疾病进展的细胞。如果斑块中炎性巨噬细胞的数量增加,
动脉粥样硬化进展为危及生命的并发症。斑块巨噬细胞来源于循环
单核细胞,而单核细胞又来自髓系祖细胞和造血干细胞。当发布到
循环中,单核细胞跟随趋化因子的梯度走向动脉粥样硬化斑块,在那里内皮细胞黏附
分子帮助它们渗入管壁。一旦进入斑块,炎性巨噬细胞就会破坏稳定
通过蛋白酶形成基质,并可能在局部死亡。或者,如果当地环境允许,巨噬细胞可以
获得较少的炎症表型,促进胆固醇的清除和组织修复。这些洞察力具有
很难转化为临床有用的疗法,部分原因是广泛的抗炎疗法可能
损害免疫细胞和宿主防御的有益功能。目标就是。在本应用程序中,我们的目标是
利用体内RNA干扰创建一类新的巨噬细胞靶向动脉粥样硬化治疗药物
(RNAi)。我们将针对作为关键决策节点的离散蛋白质设计小干扰RNA(siRNA
巨噬细胞的命运。我们建议干预巨噬细胞的生命周期,目的是支持
动脉粥样硬化斑块中的炎症消退。我们将测试中心假设,RNAi可以是
被用来设计治疗炎性动脉粥样硬化的精确疗法。我们将通过以下方式验证这一假设
靶向巨噬细胞诞生所必需的蛋白质(沉默转录因子MTG16和PU.1,
影响造血干细胞和内皮细胞在造血龛中的活性、迁移
(沉默单核细胞的趋化因子受体和内皮细胞的黏附分子),成熟
(沉默单核细胞向巨噬细胞分化所必需的M-CSF受体)和极化
(沉默产生炎症性M1巨噬细胞的基本转录因子IRF5
函数)。创新。我们将使用新的纳米材料将其输送到髓系、祖细胞和内皮细胞,
新的和尚未确定的siRNA序列,并针对在
巨噬细胞的生命周期。冲击力。我们将开发新的疗法来抑制炎性巨噬细胞的活动
在动脉壁上。我们将在心肌梗塞后加速的小鼠中确定一种成功的治疗策略
动脉粥样硬化,一种模拟需要积极治疗干预的脆弱患者的情景。
我们的最终目标是将这些材料带入临床,改善目前不足的护理标准
通过更好地二级预防心肌梗死和中风。
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(2)
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DANIEL G ANDERSON其他文献
DANIEL G ANDERSON的其他文献
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{{ truncateString('DANIEL G ANDERSON', 18)}}的其他基金
Nonviral delivery techniques for in vivo prime editing
用于体内引物编辑的非病毒传递技术
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Nonviral delivery techniques for in vivo prime editing
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SMART BIOELECTRONIC IMPLANTS FOR CONTROLLED DELIVERY OF THERAPEUTIC PROTEINS IN VIVO AND ITS APPLICATION IN LONG-TERM TREATMENT OF HEMOPHILIA A
用于体内治疗性蛋白质控制输送的智能生物电子植入物及其在血友病 A 长期治疗中的应用
- 批准号:
10615840 - 财政年份:2022
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Combinatorial and computational design of bnAb mRNA vaccines for HIV
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Combinatorial and computational design of bnAb mRNA vaccines for HIV
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Develop combinatorial non-viral and viral CRISPR delivery for lung diseases
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高通量微流控细胞内递送平台
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High throughput microfluidic intracellular delivery platform
高通量微流控细胞内递送平台
- 批准号:
8839787 - 财政年份:2013
- 资助金额:
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