Hematopoiesis in cardiovascular disease

运输和信息交换是血液的主要功能。如果氧气的运输受到 动脉粥样硬化血栓闭塞，下游缺氧细胞和组织在几分钟内开始死亡，如果任其发展 如果不治疗，这种生物体可能会死于心肌梗死(MI)或中风。细胞血液成分， 包括单核细胞和中性粒细胞，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袭，但也可能攻击 心血管组织，导致动脉粥样硬化斑块发炎、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，炎症是心血管残余风险的主要因素 因此，对当代心肌梗死的发病起决定性作用。因为炎症是 目前没有针对心血管临床护理，这一未使用的免疫治疗机会，这表明 在自身免疫和肿瘤疾病方面大有希望，可能是治疗缺血性心脏的下一个前沿 疾病。为了解决这一巨大的未得到满足的临床需求，我们建议从炎症的根源入手：白细胞 生产，即造血术。造血、白血球计数和 心血管疾病死亡。造血功能的改变改变了先天免疫细胞的生成率和表型， 因此可能会保护或攻击心血管器官。反之亦然，血液的生成受 心血管危险因素和疾病。例如，造血组织被微妙地血管化和 因此与血液传播的信息密切相关。新出现的数据表明，高脂血症和 急性心肌梗塞激活了整个造血树，包括上游干细胞。然而，尽管长期以来- 已知白细胞增多症与心血管疾病之间的联系，令人惊讶的是，对这种疾病中的骨髓知之甚少。 布景。这一知识鸿沟可能源于心血管和血液学的传统分离 纪律。目前，真正研究CDV造血的跨学科团队还很少。科学家们 将在涉及的字段之间建立缺失的链接，连接 血液学(斯卡登)、先天免疫(Swirski)、缺血性心脏病(Nahrdorf)、定量 细胞群体动力学建模(NOWAK)、基因编辑(Joung)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效应和临界质量 骨髓是心血管死亡率的驱动因素，这是一个全新的视角。我们在4分钟内组织了一支队伍 项目和3个核心，它们从两个互补的优势点共同追求我们的整体使命：1.什么 干细胞固有的病理，包括遗传和表观遗传改变，会导致白细胞增多和 心血管器官的炎症？2.心血管疾病如何改变造血和 产生的白细胞的表型？这四个项目将追求这两个视角，重点放在共同的 损伤动脉壁和心脏的炎性免疫细胞产量增加的终点。

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.