Stress-induced trained immunity in cardiovascular disease

心血管疾病中压力诱导的免疫力训练

• 批准号: 10635427
• 负责人: Willem Mulder
• 金额: $ 53.46万
• 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 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635427
• 关键词: Arteriogram; Atherosclerosis; Biological Assay; Bone Marrow; Bone Marrow Aspiration; Bone Marrow Transplantation; Cardiovascular Diseases; Cardiovascular system; Catecholamines; Cell Compartmentation; Cell Reprogramming; Cells; Chronic; Chronic stress; Coronary Arteriosclerosis; Coronary artery; Development; Disease; Epigenetic Process; Event; Exposure to; Familial Hypercholesterolemia; Glucocorticoids; Heart failure; Hematopoietic; Hematopoietic stem cells; Hormones; Human; Image; Immune; Immunity; Immunologic Memory; In Vitro; Infection; Inflammation; Inflammatory; Innate Immune System; Intervention; Ligation; Metabolic; Methods; Modification; Multiomic Data; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; Myocardial Infarction; Outcome; Patients; Peripheral; Phenotype; Pheochromocytoma; Positron-Emission Tomography; Psychosocial Stress; Questionnaires; Reporting; Rest; Risk Factors; Sampling; Sterility; Stimulus; Stress; System; Testing; Therapeutic; Training; Vaccination; Work; biobank; cardiovascular risk factor; clinical imaging; clinical translation; cohort; experience; fluorodeoxyglucose positron emission tomography; high risk; hormonal signals; human model; immune imaging; in vivo; insight; monocyte; mouse model; multiple omics; nanobiologic; optogenetics; oxidized low density lipoprotein; perceived stress; profiles in patients; progenitor; programs; recruit; stem cells

PROJECT SUMMARY In the last decade, emerging evidence has unveiled that the innate immune system retains long- term epigenetic and metabolic changes after infection or vaccination. This de facto innate immune memory has been termed ‘trained immunity’ and is characterized by myeloid cells’ hyper-responsiveness following a subsequent stimulus. Recent work has shown that sterile atherogenic/inflammatory triggers, such as oxidized LDL or catecholamines, similarly induce a trained immunity phenotype through epigenetic and metabolic reprogramming of the myeloid compartment. The long-term persistence of trained immunity in vivo is due to the reprogramming of hematopoietic stem and progenitor cells (HSPC) in the bone marrow. We have recently reported that monocytes isolated from patients with risk factors for CVD, such as familial hypercholesterolemia or pheochromocytoma, display a ‘trained’ phenotype. Importantly, in patients with established coronary artery disease, we found HSPCs reprogrammed towards a pro-inflammatory myeloid lineage. Project 2 will focus on stress-induced trained immunity’s mechanistic aspects in cardiovascular disease patients and mouse models. Our central hypothesis is that chronic stress induces trained immunity via HSPC reprogramming, which exacerbates the development of atherosclerosis and worsens the outcome of cardiovascular events. In Aim 1, we will use deep phenotyping and imaging to study patients at high risk for cardiovascular events in order to obtain an integrated view of stress-induced reprogramming of the myeloid cell compartment. In Aim 2, we will study mice that were exposed to chronic mild psychosocial stress or to key hormonal signals that promote peripheral effects on stress, followed by a rest period of 4 weeks. After the rest period, stressed cohorts and non-stressed controls will undergo coronary artery ligation or induction of atherosclerosis to test the hypothesis that preceding stress or exposure to stress hormones activates trained immunity, thus increasing myelopoiesis and consequently worsening cardiovascular disease. Our unique ability to profile patients’ HSPCs at Radboudumc, the human models, and the mouse models that mimic them will yield critical insights into the relationship between cardiovascular disease and psychosocial stress.

项目概要 在过去的十年中，新出现的证据表明，先天免疫系统保留了长期的免疫功能。 感染或疫苗接种后的术语表观遗传和代谢变化，实际上是先天免疫记忆。 被称为“训练有素的免疫”，其特征是骨髓细胞在 最近的研究表明，无菌性动脉粥样硬化/炎症触发因素，例如 氧化的低密度脂蛋白或儿茶酚胺，同样通过表观遗传和诱导训练的免疫表型 骨髓训练隔室的代谢重编程免疫的长期持续性。 体内是由于骨髓中造血干细胞和祖细胞（HSPC）的重新编程所致。 我们最近报道，从具有 CVD 危险因素的患者中分离出单核细胞，例如 家族性高胆固醇血症或嗜铬细胞瘤，在患者中表现出“训练有素”的表型。 对于已确诊的冠状动脉疾病，我们发现 HSPC 被重新编程为促炎细胞 项目 2 将重点关注应激诱导的训练免疫的机制方面。 我们的中心假设是慢性压力会诱发心血管疾病患者和小鼠模型。 通过HSPC重编程训练免疫力，这会恶化动脉粥样硬化的发展 使心血管事件的结果恶化。 在目标 1 中，我们将使用深度表型分析和成像技术来研究心血管高风险患者 事件以获得应激诱导的骨髓细胞重编程的综合视图 在目标 2 中，我们将研究暴露于慢性轻度社会心理压力或钥匙的小鼠。 促进外周压力影响的荷尔蒙信号，然后是 4 周的休息期。 休息期间，应激组和非应激对照组将接受冠状动脉结扎或诱导 动脉粥样硬化，以检验先前的压力或暴露于压力荷尔蒙会激活的假设 训练免疫力，从而增加骨髓细胞生成，从而恶化心血管疾病。 我们在 Radboudumc 分析患者 HSPC、人体模型和小鼠的独特能力 模仿它们的模型将对心血管疾病和心血管疾病之间的关系产生重要的见解。 社会心理压力。