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 克隆造血（CH）源于造血干细胞中生长优势的体细胞突变。尽管 增加血液系统恶性肿瘤的风险，出乎意料的CH还增加了心肌梗塞和 中风。 CH从40岁开始时增加频率，并存在于70岁以上的10％以上的人中 作为动脉粥样硬化心血管疾病（CVD）的主要非传统危险因素。在四个普通遗传中 与CH相关的变体，JAK2V617F（JAK2VF）突变，它增加了JAK/Stat Signal传导IMPPARTS增加了12倍 冠心病的危险比。这些最近的观察结果强调了发展精度的绝对当务之急 这些患者治疗CVD的医学策略。我们报告说，骨髓中携带JAK2VF突变的小鼠 细胞暴露增加了动脉粥样硬化和炎症体激活。在小鼠中的初步研究进一步揭示了 在动脉粥样硬化病变中，JAK2VF巨噬细胞（Mφ）增加了IL-1介导的增殖。为了建模我们 利用了混合的骨髓移植模型，其中20％的骨髓细胞带有JAK2VF突变，并且 剩余的80％是野生型。在这些JAK2VF-CH小鼠中，JAK2VF存在于约25％的CD45+血细胞中，但是在病变中 JAK2VF包括50％的CD45+细胞，因此代表斑块中的克隆膨胀。通过这里提出的目标， 我们将检验以下假设：在CH的JAK2VF模型中，炎性体激活增加导致IL-1β增加 潜在的分泌物？增殖，凋亡和动脉粥样硬化。 AIM 1将检验以下假设。 JAK2VF-CH的高胆固醇驱动的模型，IL-1β抗体的给药会导致JAK2VFMφ下降？ 增殖，较少的mφ？积累和较小的病变。此外，我们以前报道了JAK2VF小鼠 坏死核的形成增加，最近我们发现CASPASE1/11的缺失使坏死核归一化 JAK2VF小鼠的区域，表明毒气素D的下游激活介导的凋亡增加。 特定的目标2将通过繁殖GSDMD - / - 小鼠来检查凋亡对坏死核心形成的贡献。 JAK2VF小鼠并检查JAK2VF依赖性信号传导机制，该机制可能导致凋亡增加。成功的 拟议的研究的完成将增强我们对驱动机制的理解增加了动脉粥样硬化 JAK2VF介导的ch。利用IL-1β抗体的研究？可以为考虑在 人类。