Preclinical imaging of immune responses to chronic stress

对慢性应激的免疫反应的临床前成像

基本信息

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
项目类别：
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

项目摘要

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.

概括社会心理压力在多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，我们旨在调查急性和慢性压力暴露及其对免疫系统的直接和长期影响动脉粥样硬化。我们将通过开发和应用非 - 侵入性成像方法。应力激活大脑中的潜水员信号通路，包括下丘脑 - 垂体 - 肾上腺（HPA）轴和交感神经系统（SNS），随后影响白细胞分布和功能以及动脉粥样硬化斑块炎症。具体而言，急性应力对照过程中的HPA轴激活淋巴细胞和单核细胞向骨髓寄养，而中性粒细胞迅速从骨头动员由于运动皮层信号引起的骨髓3。同时，社交媒体激活导致儿茶酚胺的生产，它诱导基于代谢和表观遗传学的单核细胞中持久的促炎表型重新线4,5。由于压力引起的SNS激活也已与增强的动脉粥样硬化斑块直接相关炎症6,7。在慢性应激暴露期间，直接交感的信号传导增强了骨髓（造血）中的造血茎和祖细胞（HSPC），导致较高循环促炎性嗜中性粒细胞和单核细胞的数量6,8。这些细胞随后外观进入动脉壁并增强牙菌斑注射。我们假设压力暴露会通过诱导训练的免疫力和髓样细胞动力学的变化。在这个高度创新的项目中，我们将员工新开发和建立的宠物成像方法，以探测压力对免疫的影响系统和动脉粥样硬化斑块炎症纵向，体内和全身水平。在AIM 1中，我们将重点放在造血器官中的代谢和表观遗传学上，并在压力暴露过程中压力退出后。 AIM 2围绕压力诱导的髓样细胞动力学改变（细胞）通过复杂的成像方法探测的增殖，迁移，出口和髓样细胞负担）。完成这些目标将有助于破译压力对免疫的立即和长期影响系统虽然分子生物学和免疫学与最先进的翻译的独特整合心血管成像研究。