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.

项目总结