Clonal hematopoiesis, inflammasomes and atherosclerosis

克隆造血、炎症小体和动脉粥样硬化

• 批准号: 10339390
• 负责人: ALAN richard TALL
• 金额: $ 54.41万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10339390
• 关键词: Age; Anti-Inflammatory Agents; Antibodies; Antibody Therapy; Antioxidants; Apoptotic; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Binding; Blood Cell Count; Bone Marrow Cells; CASP1 gene; Cardiovascular Diseases; Cell Death; Cells; Coronary heart disease; DNA; DNA Fragmentation; Defect; Elderly; Enzymes; Generations; Genetic; Genotype; Glycolysis; Goals; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Human Genetics; Impairment; Infection; Inflammasome; Inflammation; Interleukin-1; Interleukin-1 beta; Interleukin-18; JAK2 gene; Lead; Lesion; Leukocytosis; Link; Mediating; Metabolic; Mitochondria; Modeling; Mus; Mutation; Myocardial Infarction; Necrosis; Pathway interactions; Patients; Persons; Polycythemia; Population; Resistance; Respiration; Risk; Risk Factors; Role; Signal Transduction; Signaling Molecule; Somatic Mutation; Stroke; Thrombosis; Transplantation; Variant; base; cardiovascular disorder risk; cardiovascular risk factor; coronary event; density; experimental study; extracellular; gain of function; genetic variant; in vivo; loss of function; macrophage; mouse model; neutrophil; novel strategies; oxidation; premature; risk variant; single-cell RNA sequencing

Project Summary/Abstract The recent CANTOS trial showed that administration of an antibody targeting IL-1b reduced coronary events, supporting the concept of anti-inflammatory therapy as a way to reduce cardiovascular disease (CVD). However, due to a modest effect and an excess of infections this treatment has not been approved for CVD treatment. This suggests the need for new approaches and for targeting anti-inflammatory therapy to patients who need it most. Clonal hematopoiesis (CH), a highly prevalent condition in the elderly, arises from somatic mutations that endow a proliferative advantage to hematopoietic stem cells (HSCs). CH increases the risk of myocardial infarction and stroke independently of traditional risk factors and in mouse models increases macrophage (Mf) inflammation and atherosclerosis. This application will seek to elucidate mechanisms linking clonal hematopoiesis to accelerated atherosclerosis, focusing on one particular cause of CH involving a gain of function in the signaling molecule JAK2. Relative to other common genetic variants giving rise to CH, this particular variant JAK2V617F (JAK2VF) increases Jak/Stat signaling, occurs at a younger age and imparts a greater risk of premature coronary heart disease. Our recent studies have shown a key role of Mf inflammasome activation, IL- 1b secretion and Mf proliferation in promoting atherosclerosis in mice expressing Jak2VF. Il-1b antibody treatment reduced features of atherosclerotic plaque instability in a mouse model of Jak2VF CH. In human studies we showed that the myocardial infarction associated with JAK2VF is increased by a common loss of function genetic variant in LNK that normally acts to suppress JAK/STAT signaling. This proposal will use mouse models that authentically replicate the human genetic variants to elucidate the mechanisms and consequences of Jak2VF- mediated inflammasome activation in atherosclerosis and the potential modulation of these effects by Lnk. The overall hypothesis is that metabolic changes in Jak2VF Mfs lead to Aim2 inflammasome activation, Gasdermin D cleavage, IL-1 secretion, pryoptotic cell death and necrotic core formation in atherosclerotic lesions. Our studies may suggest that suggest that precise application of anti-IL-1β or anti-inflammasome therapy based on CH status and LNK genotype could substantially reduce cardiovascular risk.

项目总结/摘要 最近的CANTOS试验表明，给予靶向IL-1b的抗体可减少冠状动脉事件， 支持抗炎治疗作为减少心血管疾病（CVD）的一种方法的概念。然而，在这方面， 由于效果不佳和感染过多，该治疗尚未被批准用于CVD治疗。 这表明需要新的方法和有针对性的抗炎治疗的患者谁需要它 最多克隆性造血（CH）是老年人中一种非常普遍的疾病，由体细胞突变引起， 赋予造血干细胞（HSC）增殖优势。CH增加心肌梗死的风险 梗死和中风独立于传统的风险因素，在小鼠模型中增加巨噬细胞（Mf） 炎症和动脉粥样硬化。本申请将试图阐明克隆 造血加速动脉粥样硬化，重点是CH的一个特殊原因，涉及功能的获得 信号分子JAK 2中。相对于其他常见的遗传变异引起CH，这种特殊的 JAK 2 V617 F（JAK 2 VF）变异增加了Jak/Stat信号传导，发生在较年轻的年龄，并赋予更大的风险， 早发冠心病我们最近的研究表明，Mf炎性小体激活，IL-10， 1b分泌和Mf增殖促进表达Jak 2 VF的小鼠动脉粥样硬化。IL-1b抗体治疗 在Jak 2 VF CH小鼠模型中，动脉粥样硬化斑块不稳定性的特征减少。 结果显示，与JAK 2 VF相关的心肌梗死增加了一种常见的遗传功能丧失， LNK中的一种变体，通常用于抑制JAK/STAT信号传导。该提案将使用小鼠模型， 真实地复制人类遗传变异，以阐明Jak 2 VF的机制和后果， 介导的动脉粥样硬化炎性小体激活和潜在的调制这些影响LNK。的 总体假设是Jak 2 VF Mfs的代谢变化导致Aim 2炎性小体激活，Gasdermin D 动脉粥样硬化病变中的裂解、IL-1分泌、胞浆变性细胞死亡和坏死核心形成。我们的研究 可能提示根据CH状态精确应用抗IL-1β或抗炎体治疗 LNK基因型可显著降低心血管病风险。