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.

问题所在在过去的十年里，人们在理解免疫过程方面取得了前所未有的进展， 驱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， 动脉粥样硬化发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，其又来源于骨髓祖细胞和造血干细胞。当释放到 在循环中，单核细胞遵循趋化因子梯度朝向动脉粥样硬化斑块，其中内皮粘附 分子帮助它们外渗到血管壁中。一旦进入斑块，炎症巨噬细胞就会不稳定 基质通过蛋白酶，并可能局部死亡。或者，如果局部环境允许，巨噬细胞可以 获得较少的炎症表型，促进胆固醇去除和组织修复。这些见解 很难转化为临床上有用的治疗方法，部分原因是广泛的抗炎治疗可能 损害免疫细胞和宿主防御的有益功能。目标.在本申请中，我们的目标是 使用体内RNA干扰创建一类新的巨噬细胞靶向动脉粥样硬化治疗剂 （RNAi）。我们将设计小干扰RNA（siRNA）靶向离散蛋白质，这些蛋白质是关键决策节点 巨噬细胞的命运我们建议干扰巨噬细胞的生命周期，目的是支持 动脉粥样硬化斑块炎症消退。我们将测试中心假设，即RNAi可以 用来设计炎性动脉粥样硬化的精确疗法。我们将通过以下方式检验这一假设： 靶向巨噬细胞出生所必需的蛋白质（沉默转录因子MTG 16和PU.1， 影响造血干细胞和造血小生境中内皮靶的活性）、迁移 （沉默单核细胞中的趋化因子受体和内皮细胞中的粘附分子），成熟 （沉默单核细胞分化为巨噬细胞所必需的M-CSF受体）和极化 （沉默产生M1巨噬细胞的必需转录因子IRF 5， 职能）。创新我们将使用新的纳米材料输送到骨髓，祖细胞和内皮细胞， 新的和尚未确定的siRNA序列，并针对创新的生物靶标， 巨噬细胞生命周期冲击我们将开发新的疗法来抑制炎症巨噬细胞的活性 在动脉壁上我们将在心肌梗死后加速心肌梗死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 通过更好地对心肌梗死和中风进行二级预防。