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.

项目摘要/摘要 最近的CANTOS试验表明，靶向IL-1B的抗体的给药降低了冠状动脉事件， 支持抗炎疗法的概念，以减少心血管疾病（CVD）。然而， 由于适度的作用和过量感染，该治疗尚未批准用于CVD治疗。 这表明需要采用新方法并针对需要它的患者靶向抗炎疗法 最多。克隆造血（CH）是一种高度普遍的状态，是由体细胞突变引起的 赋予造血干细胞（HSC）的增殖剂优势。 CH增加了心肌的风险 梗塞和中风独立于传统的危险因素，而在小鼠模型中则增加了巨噬细胞（MF） 炎症和动脉粥样硬化。该应用程序将寻求阐明连接克隆的机制 造血加速动脉粥样硬化，重点是涉及功能的特定原因 在信号分子JAK2中。相对于其他常见的遗传变异，引起了CH 变体JAK2V617F（JAK2VF）增加了JAK/Stat信号，发生在年龄较小，并带来更大的风险 过早的冠心病。我们最近的研究表明，MF炎性体激活，IL-的关键作用 1B表达JAK2VF的小鼠动脉粥样硬化的1B分泌和MF增殖。 IL-1B抗体处理 在JAK2VF CH的小鼠模型中，动脉粥样硬化斑块不稳定性的特征降低。在人类研究中 表明与JAK2VF相关的心肌梗塞通过功能通用的常见丧失增加了 LNK中通常可抑制JAK/Stat信号的变体。该建议将使用鼠标模型 真正地复制人类遗传变异，以阐明JAK2VF-的机制和后果 动脉粥样硬化中介导的炎症体激活以及LNK对这些作用的潜在调节。这 总体假设是JAK2VF MFS的代谢变化导致AIM2炎性体激活，Gasdermin d 动脉粥样硬化病变中的裂解，IL-1分泌，促凋亡细胞死亡和坏死核心形成。我们的研究 可能表明，基于CH状态的抗IL-1β或抗炎症疗法的精确应用 LNK基因型可以大大降低心血管风险。