Stress-induced immune reprogramming in cardiovascular disease

心血管疾病中压力诱导的免疫重编程

• 批准号: 10635421
• 负责人: Zahi A. Fayad
• 金额: $ 234.61万
• 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/10635421
• 关键词: Address; Affect; Atherosclerosis; Biology; Brain; Brain region; COVID-19 pandemic; Cardiovascular Diseases; Cardiovascular system; Catecholamines; Cell Nucleus; Cell physiology; Clinical; Clinical Research; Complex; Coronary heart disease; Development; Disease; Epigenetic Process; Event; Evidence based intervention; Foundations; Genetic; Goals; Hematopoietic System; Human; Imaging Techniques; Immune; Immune system; Immunity; Immunologic Memory; Immunology; Individual; Inflammatory; Knowledge; Leukocytes; Link; Macrophage; Mediating; Methods; Modeling; Molecular; Multimodal Imaging; Mus; Myeloid Cells; Nervous System; Neuroimmune; Neurologic; Neurosciences; Pathway interactions; Patients; Principal Investigator; Psychiatry; Psychosocial Assessment and Care; Psychosocial Stress; Reaction; Research; Research Personnel; Residual state; Risk Management; Stress; Thinking; Training; Vascular System; cardiovascular risk factor; data integration; experience; image translation; imaging modality; imaging study; immunoregulation; in vitro Assay; in vivo imaging; innovation; insight; metabolic profile; monocyte; mouse model; multidisciplinary; nanobiologic; nanotherapy; new therapeutic target; novel; novel strategies; optogenetics; perceived stress; pre-clinical; programs; social defeat; therapeutic target; tool

PROJECT SUMMARY Psychosocial stress is a critical risk factor for cardiovascular disease. However, current cardiovascular risk management strategies include few evidence-based interventions to address psychosocial stress’s detrimental effects on this disease. With the current global events, notably the ongoing COVID-19 pandemic and the increasing burden of atherosclerotic heart disease, modulating stress’ effects is warranted. The goal of our current proposal is mechanistically understanding psychosocial stress’s impact on the immune system and inflammatory atherosclerosis to lower residual cardiovascular risk in patients. Over the course of our Type-1 Program, we substantially contributed to knowledge about the links between psychosocial stress and cardiovascular disease by identifying tissular, cellular, and molecular pathways that connect nervous, immune, and vascular systems. Specifically, we found that stress perception mechanisms influence atherosclerosis development and regression. We developed sophisticated tools to study specific brain regions and their contributions to stress perception. We made substantial progress on translational imaging studies in atherosclerosis. In clinical studies, we are gaining ground on understanding the neuro-immune-arterial pathway. Our collaborative efforts to studying how stress affects the immune system have yielded new, innovative research questions we are now eager to explore. Drawing on our Type-1 Program, in the current proposal, we will not merely investigate macrophage biology; we will broaden our scope to acquire a complete picture of immune reprogramming in psychosocial stress-aggravated atherosclerotic disease. Our Program’s broader perspective includes more expansively evaluating different brain circuits and employing a wide variety of imaging methods while pursuing more in-depth analyses (omics) and optimal data integration. This innovative approach will elevate our understanding of the complex interrelation between stress perception and cardiovascular immunology, simultaneously extending the Program’s clinical scope. We will approach this highly innovative program with our multidisciplinary team including the previous program’s principal investigators, most of its key investigators, as well as new collaborators in neuroscience, psychiatry, and trained immunity. Our program will yield critical insights into how stress- induced immune reprogramming exacerbates (ongoing) cardiovascular disease. Its successful completion will not only lay the foundation for unique (i) scientific insights into immune mechanisms that are regulated neurologically and drive cardiovascular disease development but also yield (ii) a forward-thinking approach to managing cardiovascular disease in individuals experiencing prolonged episodes of psychosocial stress and identify novel (iii) therapeutic targets and treatments.

项目概要 社会心理压力是心血管疾病的关键危险因素。然而，目前 心血管风险管理策略包括很少的循证干预措施来解决 社会心理压力对这种疾病的有害影响。随着当前的全球事件，特别是 持续的 COVID-19 大流行和动脉粥样硬化性心脏病的负担日益增加， 压力的影响是有道理的。我们当前提案的目标是机械地理解心理社会 压力对免疫系统和炎性动脉粥样硬化的影响，以降低残余心血管 患者的风险。 在我们的 Type-1 计划过程中，我们为有关链接的知识做出了巨大贡献 通过识别组织、细胞和分子来确定社会心理压力和心血管疾病之间的关系 连接神经、免疫和血管系统的途径。具体来说，我们发现压力 感知机制影响动脉粥样硬化的发展和消退。我们开发了 研究特定大脑区域及其对压力感知的贡献的复杂工具。我们做了 动脉粥样硬化转化成像研究取得实质性进展。在临床研究中，我们正在获得 以理解神经-免疫-动脉通路为基础。 我们共同努力研究压力如何影响免疫系统，取得了新的成果， 我们现在渴望探索创新的研究问题。借鉴我们的 Type-1 计划，在当前 建议，我们不仅仅研究巨噬细胞生物学；我们将扩大我们的范围以获得 心理社会压力加剧的动脉粥样硬化疾病中免疫重编程的全貌。我们的 该计划的更广泛的视角包括更广泛地评估不同的大脑回路并采用 多种成像方法，同时追求更深入的分析（组学）和最佳数据 一体化。这种创新方法将提高我们对两者之间复杂相互关系的理解 压力感知和心血管免疫学，同时扩展了该计划的临床范围。 我们将与我们的多学科团队一起实施这一高度创新的计划，其中包括 之前项目的主要研究人员、大多数关键研究人员以及新的合作者 神经科学、精神病学和训练有素的免疫力。我们的计划将产生关于压力如何影响的重要见解 诱导的免疫重编程会加剧（持续的）心血管疾病。其顺利完成 不仅将为独特的（i）对受监管的免疫机制的科学见解奠定基础 神经病学并推动心血管疾病的发展，但也产生（ii）前瞻性的方法 控制经历长期社会心理压力的个体的心血管疾病 并确定新的 (iii) 治疗靶点和治疗方法。

项目成果

Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells.

• DOI: 10.1038/s41551-023-01050-0
• 发表时间: 2023-09
• 期刊: Nature biomedical engineering
• 影响因子: 28.1

Imaging-guided nanomedicine development.

• DOI: 10.1016/j.cbpa.2021.01.014
• 发表时间: 2021-08
• 期刊: Current opinion in chemical biology
• 影响因子: 7.8
• 作者: Bernal A;Calcagno C;Mulder WJM;Pérez-Medina C
• 通讯作者: Pérez-Medina C

Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance.

• DOI: 10.1016/j.immuni.2018.09.008
• 发表时间: 2018-11-20
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Braza MS;van Leent MMT;Lameijer M;Sanchez-Gaytan BL;Arts RJW;Pérez-Medina C;Conde P;Garcia MR;Gonzalez-Perez M;Brahmachary M;Fay F;Kluza E;Kossatz S;Dress RJ;Salem F;Rialdi A;Reiner T;Boros P;Strijkers GJ;Calcagno CC;Ginhoux F;Marazzi I;Lutgens E;Nicolaes GAF;Weber C;Swirski FK;Nahrendorf M;Fisher EA;Duivenvoorden R;Fayad ZA;Netea MG;Mulder WJM;Ochando J
• 通讯作者: Ochando J

Targeting Trained Innate Immunity With Nanobiologics to Treat Cardiovascular Disease.

• DOI: 10.1161/atvbaha.120.315448
• 发表时间: 2021-06
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Teunissen AJP;van Leent MMT;Prévot G;Brechbühl EES;Pérez-Medina C;Duivenvoorden R;Fayad ZA;Mulder WJM
• 通讯作者: Mulder WJM

Antibody-Mediated Inhibition of CTLA4 Aggravates Atherosclerotic Plaque Inflammation and Progression in Hyperlipidemic Mice.

• DOI: 10.3390/cells9091987
• 发表时间: 2020-08-29
• 期刊: Cells
• 影响因子: 6
• 作者: Poels K;van Leent MMT;Reiche ME;Kusters PJH;Huveneers S;de Winther MPJ;Mulder WJM;Lutgens E;Seijkens TTP
• 通讯作者: Seijkens TTP