Clonal hematopoiesis, inflammasomes and atherosclerosis

项目摘要/摘要 最近的CANTOS试验表明，注射一种针对IL-1b的抗体可以减少冠状动脉事件， 支持将抗炎治疗作为减少心血管疾病(CVD)的一种方式的概念。然而， 由于疗效不大，感染过多，这种疗法尚未被批准用于心血管疾病的治疗。 这表明有必要采用新的方法，并针对需要抗炎治疗的患者进行针对性治疗。 大多数都是。克隆性造血(CH)是一种在老年人中高度流行的疾病，由体细胞突变引起 赋予造血干细胞(HSCs)增殖优势。先天性心脏病增加心肌梗死的风险 独立于传统危险因素的脑梗塞和中风以及在小鼠模型中巨噬细胞(MF)的增加 炎症和动脉粥样硬化。这项应用将试图阐明克隆人之间的联系机制 造血到加速的动脉粥样硬化，集中在一个涉及功能获得的特定原因的CH 在信号分子JAK2中。相对于其他导致CH的常见遗传变异，这一特殊的 变异JAK2V617F(JAK2VF)增加JAK/STAT信号，发生在更年轻的年龄，并赋予更大的风险 早产儿冠心病。我们最近的研究表明，MF炎症体激活的关键作用是IL-1。 1B分泌和MF增殖促进Jak2VF表达小鼠动脉粥样硬化IL-1b抗体治疗 在Jak2VF CH小鼠模型中动脉粥样硬化斑块不稳定性的减少特征。在人类研究中，我们 显示与JAK2VF相关的心肌梗死是通过常见的功能遗传丧失而增加的 LNK的变体，通常用于抑制JAK/STAT信号。这项提议将使用鼠标模型， 真实复制人类基因变异，以阐明Jak2VF的机制和后果- 动脉粥样硬化中介导的炎性小体激活以及LNK对这些效应的潜在调节。这个 总体假设是Jak2VF MFS的代谢变化导致AIM2炎症体激活，Gasdermin D 动脉粥样硬化病变中的卵裂、IL-1分泌、变性细胞死亡和坏死核的形成。我们的研究 提示准确应用抗IL-1β或根据CH状态进行抗炎治疗 LNK基因可显著降低心血管风险。

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.