Hematopoiesis in cardiovascular disease

心血管疾病中的造血作用

• 批准号: 10670731
• 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/10670731
• 关键词: Acute myocardial infarction; Address; Arterial Fatty Streak; Atherosclerosis; Autoimmune; Blood; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Cell Hypoxia; Cell model; Cells; Cessation of life; Circulation; Clinical; Clonal Expansion; Clonality; Clone Cells; Communication; 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; Oncology; Organ; Organism; Output; Pathogenesis; Pathology; Patients; Penetration; Peripheral; Phenotype; Population Dynamics; Positioning Attribute; Production; Proliferating; Reperfusion Therapy; Research; Residual state; Role; Scientist; Signal Transduction; Stochastic Processes; Stroke; Therapeutic; Tissues; Training; Trees; Vascularization; 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。如果氧气运输受到干扰 动脉粥样硬化闭塞，下游缺氧细胞和组织在几分钟内开始死亡，如果留下 如果不加以治疗，有机体可能会死于心肌梗塞（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 是在骨髓中产生的。先天免疫细胞可以保护我们免受病原体侵害，但也可能会攻击 心血管组织，引起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，炎症在心血管残余风险中占主导地位 疾病，从而对当代 MI 的发病机制起到决定性作用。因为炎症是 目前尚未成为心血管临床护理的目标，这种未使用的免疫治疗机会表明 在自身免疫和肿瘤疾病方面有着巨大的前景，可能是治疗缺血性心脏的下一个前沿领域 疾病。为了解决这一巨大的未满足的临床需求，我们建议找到炎症的根源：白细胞 生产，即造血。造血、白细胞计数和血细胞计数之间存在着紧密的相互作用。 心血管死亡。造血作用的改变改变了先天免疫细胞的生产率和表型， 因此可能会保护或攻击心血管器官。反之亦然，造血受以下因素影响 心血管危险因素和疾病。例如，造血组织具有精细的血管化和 因此与血液传播的信息密切相关。新数据表明，高脂血症和 急性心肌梗死会激活整个造血树，包括上游干细胞。然而，尽管长期以来 已知白细胞增多症与 CVD 之间存在关联，但令人惊讶的是，人们对这种疾病中的骨髓知之甚少 环境。这种知识差距可能是由于传统上心血管学和血液学的分离造成的 学科。目前，真正研究CDV造血作用的跨学科团队还很少。科学家们 在这个应用程序中联合起来将在所涉及的领域之间建立缺失的链接，连接 血液学 (Scadden)、先天免疫 (Swirski)、缺血性心脏病 (Nahrendorf)、定量领域的领导者 细胞群动态建模 (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。我们将团队组织为4 项目和 3 个核心，从两个互补的有利角度共同追求我们的总体使命： 1. 什么 干细胞内在病理学，包括遗传和表观遗传改变，导致白细胞增多和 心血管器官有炎症吗？ 2. 心血管疾病如何改变造血功能和 产生的白细胞的表型？这四个项目将追求两种观点，重点关注共同点 终点是损伤动脉壁和心脏的炎症免疫细胞输出增加。

项目成果

Making the cut with PAMless CRISPR-Cas enzymes.

• DOI: 10.1016/j.tig.2021.09.002
• 发表时间: 2021-12
• 期刊: TRENDS IN GENETICS
• 影响因子: 11.4
• 作者: Christie, Kathleen A.;Kleinstiver, Benjamin P.
• 通讯作者: Kleinstiver, Benjamin P.

Evolution of CRISPR-associated endonucleases as inferred from resurrected proteins.

• DOI: 10.1038/s41564-022-01265-y
• 发表时间: 2023-01
• 期刊: Nature microbiology
• 影响因子: 28.3

Recent Advances in Double-Strand Break-Free Kilobase-Scale Genome Editing Technologies.

• DOI: 10.1021/acs.biochem.2c00311
• 发表时间: 2022-09
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Connor J. Tou;B. Kleinstiver

Immunomodulation of the donor lung with CRISPR-mediated activation of IL-10 expression.

• DOI: 10.1016/j.healun.2023.06.001
• 发表时间: 2023-10
• 期刊: JOURNAL OF HEART AND LUNG TRANSPLANTATION
• 影响因子: 8.9
• 作者: Mesaki, Kumi;Juvet, Stephen;Yeung, Jonathan;Guan, Zehong;Wilson, Gavin W.;Hu, Jim;Davidson, Alan R.;Kleinstiver, Benjamin P.;Cypel, Marcelo;Liu, Mingyao;Keshavjee, Shaf
• 通讯作者: Keshavjee, Shaf

The coalescent tree of a Markov branching process with generalised logistic growth.

• DOI: 10.1007/s00285-022-01735-1
• 发表时间: 2022-04-05
• 期刊: JOURNAL OF MATHEMATICAL BIOLOGY
• 影响因子: 1.9
• 作者: Cheek, David