Preclinical imaging of immune responses to chronic stress

对慢性应激的免疫反应的临床前成像

• 批准号: 10718653
• 负责人: Mandy Maria Theresia van Leent
• 金额: $ 63.95万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718653
• 关键词: 18F-fluorothymidine; Acute; Affect; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Back; Biological Assay; Bone Marrow; Brain; Cardiac; Cardiovascular Diseases; Catecholamines; Cell Proliferation; Cell physiology; Cells; Chronic; Chronic stress; Complement; Coronary Arteriosclerosis; Data; Development; Disease Progression; Epigenetic Process; Event; Extravasation; Flow Cytometry; G9a histone methyltransferase; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homing; ITGAM gene; Image; Imaging Techniques; Immune; Immune response; Immune system; Immunity; Inflammation; Inflammatory; Label; Leukocytes; Link; Long-Term Effects; Lymphocyte; Metabolic; Metabolic Marker; Methods; Molecular Biology; Molecular Immunology; Monocytosis; Motor Cortex; Mus; Myeloid Cells; Nuclear; Organ; Phenotype; Positioning Attribute; Positron-Emission Tomography; Process; Production; Proliferating; Psychosocial Stress; Recovery; Research; Signal Transduction; Stress; Sympathetic Nervous System; Techniques; Tracer; Training; White Blood Cell Count procedure; Withdrawal; acute stress; beta-Chemokines; cardiovascular imaging; chemokine receptor; fluorodeoxyglucose positron emission tomography; hypothalamic-pituitary-adrenal axis; imaging approach; imaging modality; in vivo; innovation; mTOR inhibition; metabolic abnormality assessment; migration; monocyte; nanobiologic; nanobodies; nanotherapy; neutrophil; non-invasive imaging; novel; nuclear imaging; pre-clinical assessment; preclinical imaging; response; serial imaging; spatiotemporal; tomography; western diet

SUMMARY Psychosocial stress contributes to cardiovascular disease at several stages, including promoting coronary artery disease progression and acutely triggering cardiac events1,2. In this project, we aim to investigate both acute and chronic stress exposure and their immediate and long-term effects on the immune system and atherosclerosis. We will approach these important questions through the development and application of non- invasive imaging methods. Stress activates diverse signaling circuits in the brain, including the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), which subsequently affect leukocyte distribution and function as well as atherosclerotic plaque inflammation. Specifically, HPA axis activation during acute stress controls lymphocyte and monocyte homing to the bone marrow, while neutrophils are rapidly mobilized from the bone marrow due to motor cortex signaling3. In parallel, SNS activation leads to the production of catecholamines, which induce a long-lasting pro-inflammatory phenotype in monocytes based on metabolic and epigenetic rewiring4,5. SNS activation due to stress has also been directly linked to enhanced atherosclerotic plaque inflammation6,7. During chronic stress exposure, direct sympathetic signaling enhances the proliferation of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (hematopoiesis), leading to higher numbers of circulating pro-inflammatory neutrophils and monocytes6,8. These cells subsequently extravasate into the arterial wall and enhance plaque inflammation. We hypothesize that stress exposure induces long-term effects on the immune system through the induction of trained immunity and changes in myeloid cell dynamics. In this highly innovative project, we will employ newly developed and established PET imaging methods to probe stress’s effects on the immune system and atherosclerotic plaque inflammation longitudinally, in vivo, and at a whole-body level. In Aim 1, we will focus on metabolic and epigenetic rewiring in hematopoietic organs over the course of stress exposure and after stress withdrawal. Aim 2 evolves around stress-induced alterations in myeloid cell dynamics (cell proliferation, migration, egress, and myeloid cell burden), probed by sophisticated imaging methods. Completing these Aims will help decipher stress’s immediate and long-term impact on the immune system though unique integration of molecular biology and immunology with state-of-the-art translational cardiovascular imaging research.

总结 心理社会压力在几个阶段导致心血管疾病，包括促进 冠状动脉疾病进展和急性触发心脏事件1，2.在这个项目中，我们的目标是调查 急性和慢性应激暴露及其对免疫系统的直接和长期影响， 动脉粥样硬化我们将通过发展和应用非- 侵入性成像方法。 压力会激活大脑中的各种信号回路，包括下丘脑-垂体-肾上腺（HPA） 轴和交感神经系统（SNS），随后影响白细胞的分布和功能 以及动脉粥样硬化斑块炎症。具体地说，在急性应激控制期间HPA轴激活 淋巴细胞和单核细胞归巢到骨髓，而中性粒细胞迅速从骨动员 骨髓由于运动皮质信号3.同时，SNS激活导致产生儿茶酚胺， 其基于代谢和表观遗传在单核细胞中诱导持久的促炎表型 恢复4，5.由于压力引起的SNS激活也与动脉粥样硬化斑块的增强直接相关 炎症6，7.在慢性应激暴露期间，直接交感神经信号增强了 造血干细胞和祖细胞（HSPC）在骨髓（造血），导致更高的 循环促炎中性粒细胞和单核细胞的数量6，8.这些细胞随后渗出 进入动脉壁并增强斑块炎症。 我们假设，应激暴露通过免疫系统诱导长期影响。 诱导训练的免疫力和骨髓细胞动力学的变化。在这个创新的项目中，我们将 使用新开发和建立的PET成像方法来探测应激对免疫系统的影响， 系统和动脉粥样硬化斑块炎症纵向，在体内，并在全身水平。目标1： 将专注于在压力暴露过程中造血器官的代谢和表观遗传重新布线， 在减压后Aim 2围绕着应激诱导的髓样细胞动力学（细胞增殖）的改变而发展。 增殖、迁移、出口和骨髓细胞负荷），通过复杂的成像方法探测。 完成这些目标将有助于破译压力对免疫系统的直接和长期影响 系统虽然独特的整合分子生物学和免疫学与最先进的翻译 心血管成像研究。