Clonal hematopoiesis, inflammasomes and atherosclerosis

克隆造血、炎症小体和动脉粥样硬化

基本信息

批准号：
10581564
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
项目类别：
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/10581564
关键词：
Acceleration Age Anti-Inflammatory Agents Antibodies Antibody Therapy Antioxidants Apoptotic Arterial Fatty Streak Atherosclerosis Automobile Driving Binding Blood Cell Count Bone Marrow Cells Breeding CASP1 gene Cardiovascular Diseases Caspase Cell Death Cells Coronary heart disease DNA DNA Fragmentation Defect Elderly Endowment Enzymes Generations Genetic Genotype Glycolysis Goals Hematopoiesis Hematopoietic Hematopoietic stem cells Human Human Genetics IL18 gene Impairment Infection Inflammasome Inflammation Interleukin-1 Interleukin-1 beta JAK2 gene Lead Lesion Leukocytosis Link Macrophage Mediating Metabolic Mitochondria Modeling Mus Mutation Myocardial Infarction Necrosis Pathway interactions Patients Persons Polycythemia Population Proliferating Resistance Respiration Risk Risk Factors Role Signal Transduction Signaling Molecule Somatic Mutation Stroke Thrombosis Transplantation Variant cardiovascular disorder risk cardiovascular risk factor coronary event density experimental study extracellular gain of function genetic variant in vivo loss of function mouse model neutrophil novel strategies oxidation premature risk variant single-cell RNA sequencing

项目摘要

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.

项目概要/摘要最近的 CANTOS 试验表明，施用针对 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。由于效果有限且感染过多，该疗法尚未被批准用于 CVD 治疗。这表明需要新的方法以及针对有需要的患者进行抗炎治疗大多数克隆性造血（CH）是一种在老年人中非常普遍的疾病，是由体细胞突变引起的。赋予造血干细胞（HSC）增殖优势会增加心肌病的风险。梗死和中风与传统危险因素无关，并且在小鼠模型中增加巨噬细胞 (Mf) 该应用将寻求阐明克隆性的相关机制。造血加速动脉粥样硬化，重点关注涉及功能获得的 CH 的一种特定原因相对于引起 CH 的其他常见遗传变异，这种特殊的变异存在于信号分子 JAK2 中。变异 JAK2V617F (JAK2VF) 会增加 Jak/Stat 信号传导，发生在较年轻的年龄，并带来更大的风险我们最近的研究表明，Mf 炎症小体激活、IL- 发挥着关键作用。表达 Jak2VF 抗体治疗的小鼠中，Il-1b 分泌和 Mf 增殖促进动脉粥样硬化。在人类研究中，Jak2VF CH 小鼠模型的动脉粥样硬化斑块不稳定性特征降低。研究表明，与 JAK2VF 相关的心肌梗死因常见的功能遗传丧失而增加 LNK 中的变体通常会抑制 JAK/STAT 信号传导。真实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小体激活以及 Lnk 对这些作用的潜在调节。总体假设是 Jak2VF Mfs 的代谢变化导致 Aim2 炎性体激活，Gasdermin D 我们的研究涉及动脉粥样硬化病变中的裂解、IL-1 分泌、焦亡细胞死亡和坏死核心形成。可能建议根据 CH 状态精确应用抗 IL-1β 或抗炎体治疗 LNK基因型可以显着降低心血管风险。