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

• 批准号: 9412185
• 负责人: DANIEL G ANDERSON
• 金额: $ 47.74万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9412185
• 关键词: Acceleration; Acute; Anti-inflammatory; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Biological; Birth; Blood Circulation; Bone Marrow; Bone Marrow Stem Cell; Cell Adhesion Molecules; Cell Maturation; Cell Proliferation; Cells; Chemical Engineering; Cholesterol; Clinic; Clinical; Complication; Consensus; Data; Disease Progression; Drug Kinetics; Encapsulated; Endothelial Cells; Environment; Excision; Extravasation; Foam Cells; Formulation; Genes; Goals; Harvest; Hematopoietic; Hematopoietic stem cells; Host Defense; Image; Immune; Immunology; Inflammation; Inflammatory; Injections; Intercellular adhesion molecule 1; Interdisciplinary Study; Leukocytes; Life; Life Cycle Stages; Macrophage Colony-Stimulating Factor Receptor; Measures; Metabolic syndrome; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; Myocardial Infarction; Nanotechnology; Obese Mice; P-Selectin; Patients; Peptide Hydrolases; Peripheral; Peritonitis; Phenotype; Pneumonia; Precision therapeutics; Primates; Process; Production; Proliferating; Proteins; RNA Interference; RNA Sequences; Reactive Oxygen Species; Recurrence; Research Personnel; Resolution; Risk; Safety; Secondary Prevention; Signal Transduction; Small Interfering RNA; Stem cells; Stroke; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Tissues; Translating; Vascular Cell Adhesion Molecule-1; atherogenesis; chemokine; chemokine receptor; design; drug candidate; high risk; immune function; improved; in vivo; innovation; insight; knock-down; macrophage; migration; monocyte; nanomaterials; nanoparticle; nanoparticle delivery; novel; novel therapeutics; oxidized low density lipoprotein; plaque lesion; progenitor; programs; recruit; repaired; standard of care; stem cell niche; tissue repair; transcription factor; transcriptome

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。