Cardiovascular consequences of increased inflammasome activation in Jak2vf-mediated clonal hematopoiesis

Jak2vf介导的克隆造血过程中炎症小体激活增加的心血管后果

• 批准号: 9910765
• 负责人: Trevor Perawaskin Laramee Fidler
• 金额: $ 6.58万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2021-02-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910765
• 关键词: Age; Anti-Inflammatory Agents; Antibodies; Area; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Biology; Blood Cells; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Breeding; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Clonal Expansion; Coronary heart disease; Data; Development; Diet; Disease Progression; Evaluation; Exhibits; Foundations; Frequencies; Future; Glycolysis; Growth; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; In Vitro; Inflammasome; Interleukin-1; Interleukin-1 alpha; Interleukin-1 beta; Interleukin-18; Intrinsic factor; Lesion; Leukocytes; Mediating; Mitochondria; Mitochondrial DNA; Modeling; Mus; Mutation; Myocardial Infarction; Necrosis; Outcome Study; Oxides; PTPRC gene; Patients; Pharmacology; Plant Roots; Prevention approach; Reporting; Respiration; Risk; Risk Factors; Role; Secondary to; Signal Transduction; Somatic Mutation; Splenocyte; Stains; Stroke; Testing; Thrombosis; Transgenic Mice; Treatment Efficacy; Wild Type Mouse; Work; anakinra; atherogenesis; base; cardiovascular disorder prevention; cardiovascular disorder risk; cytokine; density; genetic variant; hazard; hypercholesterolemia; in vivo; macrophage; monocyte; mouse model; precision medicine; protective effect; receptor; therapeutic development; transplant model

Project Summary Clonal hematopoiesis (CH) arises from somatic mutations that impart a growth advantage in hematopoietic stem cells. While increasing the risk of hematological malignancy, unexpectedly CH also increases the risk of myocardial infarction and stroke. CH increases in frequency from age 40 onward and is present in >10% of people above the age of 70 identifying CH as a major non-traditional risk factor for atherosclerotic cardiovascular disease (CVD). Amongst the four common genetic variants associated with CH, the JAK2v617f (JAK2vf) mutation that increases JAK/STAT signaling imparts a 12-fold increased hazard ratio for coronary heart disease. These recent observations emphasize the absolute imperative to develop a precision medicine strategy to treat CVD in these patients. We have reported that mice harboring Jak2vf mutations in bone marrow cells exhibit increased atherosclerosis and inflammasome activation. Preliminary studies in mice have further revealed that within atherosclerotic lesions Jak2vf macrophages (Mφ) have increased IL-1 mediated proliferation. To model CH we utilized a mixed bone marrow transplantation model where 20% of bone marrow cells harbor Jak2vf mutations, and the remaining 80% are wild-type. In these Jak2vf-CH mice Jak2vf was present in ~25% of CD45+ blood cells, however in lesions Jak2vf comprised 50% of CD45+ cells, thus representing a clonal expansion within plaques. Through the aims proposed here, we will test the hypothesis that in a Jak2vf model of CH, increased inflammasome activation results in increased IL-1β secretion that potentiates Mφ? proliferation, pyroptosis, and atherogenesis. Aim 1 will test the hypothesis that in a hypercholesteremia-driven model of Jak2vf-CH, administration of IL-1β antibodies will result in decreased Jak2vf Mφ? proliferation, less Mφ? accumulation, and smaller lesions. Furthermore, we have previously reported Jak2vf mice have increased necrotic core formation, and recently we have discovered that deletion of Caspase1/11 normalizes necrotic core area in Jak2vf mice, suggesting increased pyroptosis mediated by downstream activation of GASDERMIN D. Therefore, Specific Aim 2 will examine the contribution of pyroptosis to necrotic core formation by breeding Gsdmd-/- mice with Jak2vf mice and examine Jak2vf-dependent signaling mechanism which may culminate in increased pyroptosis. Successful completion of the proposed studies will enhance our understanding of the mechanisms driving increased atherosclerosis in Jak2vf-mediated CH. Studies utilizing antibodies to IL-1β? may provide a foundation to consider using these therapies in humans.

项目摘要 克隆性造血（CH）是由体细胞突变引起的，体细胞突变赋予造血干细胞生长优势。而 增加血液恶性肿瘤的风险，意外地CH也增加心肌梗死的风险， 中风CH的频率从40岁开始增加，并且在70岁以上的人中存在>10%的CH 作为动脉粥样硬化性心血管疾病（CVD）的主要非传统危险因素。在四种常见的基因中， 与CH相关的JAK 2 v617 f（JAK 2 vf）突变增加JAK/STAT信号传导，使CH的表达增加12倍。 冠心病的风险比这些最近的观察结果强调，绝对有必要制定一个精确的 药物策略来治疗这些患者的心血管疾病。我们已经报道了骨髓中携带Jak 2 vf突变的小鼠 细胞表现出增加的动脉粥样硬化和炎性小体活化。对小鼠的初步研究进一步揭示， 在动脉粥样硬化病变内，Jak 2 vf巨噬细胞（Mφ）具有增加的IL-1介导的增殖。为了模型CH，我们 利用混合骨髓移植模型，其中20%的骨髓细胞携带Jak 2 vf突变， 其余80%为野生型。在这些Jak 2 vf-CH小鼠中，Jak 2 vf存在于约25%的CD 45+血细胞中，然而在病变中， Jak 2 vf包含50%的CD 45+细胞，因此代表斑块内的克隆性扩增。通过这里提出的目标， 我们将检验以下假设：在CH的Jak 2 vf模型中，炎性小体激活增加导致IL-1β增加 增强Mφ的分泌？增殖、焦亡和动脉粥样硬化形成。目标1将检验假设， 在高脂血症驱动的Jak 2 vf-CH模型中，IL-1β抗体的施用将导致Jak 2 vf Mφ？ 增殖、减少Mφ？积累和较小的病变。此外，我们以前曾报道过Jak 2 vf小鼠具有 增加坏死核心的形成，最近我们发现Caspase 1/11的缺失使坏死核心正常化， Jak 2 vf小鼠中的面积，表明GASDERMIN D下游激活介导的焦亡增加。因此，我们认为， 具体目标2将通过用以下动物饲养Gsdmd-/-小鼠来检查焦亡对坏死核心形成的贡献： Jak 2 vf小鼠，并检查Jak 2 vf依赖性信号传导机制，其可能导致增加的焦亡。成功 这些研究的完成将增强我们对动脉粥样硬化增加的机制的理解， Jak 2 vf介导的CH：利用IL-1β抗体的研究？可以为考虑使用这些疗法提供基础， 人类