Psychosocial stress' effects on macrophage dynamics in atherosclerosis

社会心理压力对动脉粥样硬化巨噬细胞动力学的影响

• 批准号: 10116447
• 负责人: Filip K Swirski
• 金额: $ 85.13万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-17 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116447
• 关键词: Affect; Animals; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Biological; Biology; Blood Cells; Bone Marrow; Cardiovascular Diseases; Cells; Cessation of life; Chronic; Clinical Treatment; Cues; Data; Development; Emigrations; Extramedullary; Goals; Hematopoietic stem cells; Human; Human Biology; Imaging Techniques; Inflammation; Intervention; Lesion; Leukocytes; Link; Lipids; Lipoproteins; Mediating; Mus; Myelopoiesis; Myocardial Infarction; NTN1 gene; Necrosis; Oxidative Stress; Pathway interactions; Patients; Post-Traumatic Stress Disorders; Process; Production; Proteolysis; Protocols documentation; Psychosocial Stress; Research Personnel; Risk Factors; Site; Spleen; Stress; Stroke; Sympathetic Nervous System; Systems Biology; Techniques; Testing; Therapeutic; Translating; chronic inflammatory disease; experimental study; imaging modality; inhibitor/antagonist; macrophage; monocyte; mouse model; nanoparticle; neuronal guidance; non-invasive imaging; peripheral blood; recruit; response; siRNA delivery; social stress; stem cells; therapeutic target; tool

SUMMARY Atherosclerosis, the underlying cause of myocardial infarction and stroke, is a lipid-driven chronic inflammatory disease characterized by lipoprotein and leukocyte accumulation in the vessel wall. Among leukocytes, monocyte-derived intimal macrophages are arguably the most decisive contributors to the development, progression, exacerbation, and regression of atherosclerosis. As key effectors of inflammation, proteolysis, oxidative stress, lipid clearance, and efferocytosis, macrophages have long been therapeutic targets for the treatment of atherosclerosis. However, macrophage content in the vessel wall is highly dynamic, relying on multiple systemic and local processes that are governed by distinct biological pathways. Recently, we showed that psychosocial stress, which potentiates cardiovascular disease (CVD), aggravates atherosclerosis by disturbing the macrophage supply chain; animals subjected to intermittent psychosocial stress developed inflamed lesions containing more numerous macrophages than controls. In this project, we will ask how stress affects mechanisms related to influx of monocytes (medullary myelopoiesis, mobilization of monocytes and stem cells, extramedullary myelopoiesis, and monocyte influx to lesions), macrophage accrual in lesions (macrophage differentiation and local proliferation), and macrophage efflux (macrophage death through apoptosis, necrosis, or secondary necrosis, and macrophage emigration). Collectively, we refer to these as macrophage dynamics. We will investigate the impact of stress on macrophage dynamics in the progression and regression of atherosclerosis, with specific focus on the sympathetic nervous system and neuronal guidance cues. We will identify the decision nodes that control processes related to macrophage dynamics with the ultimate aim of targeting them therapeutically.

概括 动脉粥样硬化是心肌梗塞和中风的根本原因，是脂质驱动的 以脂蛋白和白细胞积累为特征的慢性炎性疾病 船墙。在白细胞中，单核细胞衍生的内膜巨噬细胞可以说是最大的 对发展，进步，加剧和回归的决定性贡献者 动脉粥样硬化。作为炎症，蛋白水解，氧化应激，脂质清除率的关键效应因素， 和肾上腺细胞增多症，巨噬细胞长期以来一直是治疗的治疗靶点 动脉粥样硬化。但是，容器壁上的巨噬细胞含量是高度动态的，取决于 由不同的生物学途径控制的多个系统和局部过程。 最近，我们表明，增强心血管疾病（CVD）的社会心理压力， 通过干扰巨噬细胞供应链来加剧动脉粥样硬化；受到的动物 间歇性的社会心理压力发生了发炎的病变，其中含有更多 巨噬细胞比对照组。在这个项目中，我们将询问压力如何影响与 单核细胞的涌入（髓质骨髓病，动员单核细胞和干细胞， 髓质外骨髓病和单核细胞流向病变），巨噬细胞累积病变中的巨噬细胞 （巨噬细胞分化和局部增殖）和巨噬细胞外（巨噬细胞死亡） 通过凋亡，坏死或继发性坏死和巨噬细胞移民）。共同 我们将其称为巨噬细胞动力学。我们将调查压力对 动脉粥样硬化的进展和回归中的巨噬细胞动力学，具体焦点 在交感神经系统和神经元引导线索上。我们将确定决定 控制与巨噬细胞动力学相关的过程的节点以靶向最终目的 他们在治疗上。