Hematopoiesis in cardiovascular disease

心血管疾病中的造血作用

• 批准号: 10469349
• 负责人: Matthias Nahrendorf
• 金额: $ 244.38万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469349
• 关键词: Acute myocardial infarction; Address; Arterial Fatty Streak; Atherosclerosis; Autoimmune; Blood; Blood Circulation; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Cell Hypoxia; Cell model; Cells; Cessation of life; Clinical; Clonal Expansion; Clonality; Clone Cells; Computer Models; Data; Diagnostic; Discipline; Disease; Endothelial Cells; Epigenetic Process; Genes; Genetic; Goals; Heart; Heart Diseases; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Hyperlipidemia; Image; Immune; Immunology; Immunotherapy; Inflammation; Inflammatory; Ischemia; Knowledge; Lead; Left; Leukocytes; Leukocytosis; Link; Marrow; Mission; Mutation; Myelogenous; Myeloid Cells; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural Immunity; Organ; Organism; Output; Pathogenesis; Pathology; Patients; Peripheral; Phenotype; Plant Roots; Population Dynamics; Positioning Attribute; Production; Reperfusion Therapy; Research; Residual state; Role; Scientist; Signal Transduction; Stochastic Processes; Stroke; Therapeutic; Tissues; Training; Trees; cardiovascular disorder risk; cardiovascular risk factor; cell behavior; cell injury; clinical care; diagnostic tool; endothelial dysfunction; forging; frontier; hematopoietic tissue; innovation; mathematical model; migration; monocyte; mortality; mortality statistics; neutrophil; new therapeutic target; next generation; novel; oxygen transport; pathogen; programs; stem cell proliferation; stem cells; synergism

Transport and information exchange are the primary functions of blood. If oxygen transport is disrupted by atherothrombotic occlusion, downstream hypoxic cells and tissues begin dying within minutes, and if left untreated, the organism may succumb to myocardial infarction (MI) or stroke. The cellular blood components, including monocytes and neutrophils, are descendants of hematopoietic stem and progenitor cells (HSPC) and are made in the bone marrow. Innate immune cells defend us against pathogens but may also attack cardiovascular tissues, giving rise to inflamed atherosclerotic plaques, organ ischemia and failing myocardium. In the era of rapid reperfusion and statin therapy, inflammation dominates the residual risk of cardiovascular disease and thus decisively contributes to the pathogenesis of contemporary MI. Because inflammation is currently not targeted by cardiovascular clinical care, this unused opportunity for immunotherapy, which shows great promise in autoimmune and oncological diseases, is likely the next frontier in treating ischemic heart disease. To address this large unmet clinical need, we propose to go to the root of inflammation: leukocyte production, i.e. hematopoiesis. There is a tight interaction of hematopoiesis, white blood count and cardiovascular death. Altered hematopoiesis changes production rates and phenotypes of innate immune cells, which may consequently protect or attack cardiovascular organs. Vice versa, hematopoiesis is influenced by cardiovascular risk factors and disease. For instance, hematopoietic tissues are exquisitely vascularized and therefore intimately connected to blood borne information. Emerging data indicate that hyperlipidemia and acute MI activate the entire hematopoietic tree, including upstream stem cells. However, despite the long- known association between leukocytosis and CVD, surprisingly little is known about the marrow in this disease setting. This knowledge gap likely arose from the traditional separation of cardiovascular and hematology disciplines. Currently, there are few truly interdisciplinary team studying hematopoiesis in CDV. The scientists that are joining force in this application will build the missing link between the involved fields, connecting leaders in hematology (Scadden), innate immunity (Swirski), ischemic heart disease (Nahrendorf), quantitative modeling of cell population dynamics (Nowak), gene editing (Joung) and hematopoiesis imaging (Lin). This unique combination of complementary expertise creates the synergy and critical mass to study the bone marrow as a driver of cardiovascular mortality, a thoroughly novel perspective. We organize the team in 4 projects and 3 cores, which jointly pursue our overall mission from two complimentary vantage points: 1. What stem cell-intrinsic pathologies, including genetic and epigenetic alterations, cause leukocytosis and inflammation in cardiovascular organs? 2. How does cardiovascular disease change hematopoiesis and the phenotype of produced leukocytes? The four projects will pursue both perspectives, focusing on the common end point of increased output of inflammatory immune cells that damage the arterial wall and the heart.

运输和信息交换是血液的主要功能。如果氧气运输被 动脉粥样硬化血栓闭塞，下游缺氧细胞和组织开始死亡的几分钟内，如果离开 未经治疗，该生物体可能死于心肌梗塞（MI）或中风。细胞血液成分， 包括单核细胞和嗜中性粒细胞，是造血干细胞和祖细胞（HSPC）的后代， 都是在骨髓中产生的先天免疫细胞保护我们免受病原体的侵害，但也可能攻击 心血管组织，引起发炎的动脉粥样硬化斑块、器官缺血和心肌衰竭。 在快速再灌注和他汀类药物治疗的时代，炎症在心血管疾病的剩余风险中占主导地位。 疾病，因此决定性地有助于当代MI的发病机制。因为炎症是 目前没有心血管临床护理的目标，这是免疫治疗的未使用的机会， 在自身免疫性疾病和肿瘤疾病中有很大的前景，可能是治疗缺血性心脏病的下一个前沿领域。 疾病为了解决这个巨大的未满足的临床需求，我们建议去炎症的根源：白细胞 生产，即造血。造血、白色血细胞计数和 心血管死亡改变的造血改变了先天免疫细胞的产生速率和表型， 其可因此保护或攻击心血管器官。反之亦然，造血受 心血管危险因素和疾病。例如，造血组织血管发达， 因此与血液传播的信息密切相关。新的数据表明，高脂血症和 急性心肌梗死激活整个造血树，包括上游干细胞。尽管长期以来- 尽管白细胞增多症和CVD之间的关系是已知的，但令人惊讶的是，对这种疾病中的骨髓知之甚少 设置.这种知识差距可能是由于心血管和血液学的传统分离造成的 学科目前，很少有真正的跨学科团队研究CDV中的造血。科学家 在这个应用程序中加入力量将建立相关领域之间的缺失环节， 血液学（Scadden）、先天免疫（Swirski）、缺血性心脏病（Naurdorf）、定量 细胞群体动力学建模（Nowak）、基因编辑（Jardin）和造血成像（Lin）。这 互补专业知识的独特组合创造了研究骨骼的协同作用和临界质量 骨髓作为心血管死亡率的驱动因素，这是一个全新的观点。我们组织团队在4 项目和3个核心，共同追求我们的整体使命从两个互补的Vantage位置：1。什么 干细胞内在病理，包括遗传和表观遗传改变，引起白细胞增多， 心血管器官的炎症2.心血管疾病是如何改变造血功能的， 产生的白细胞的表型？这四个项目将从这两个角度出发，侧重于共同点， 炎症免疫细胞的增加输出的终点，其损害动脉壁和心脏。