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.

项目概要 克隆造血（CH）源自体细胞突变，赋予造血干细胞生长优势。 增加血液系统恶性肿瘤的风险，出乎意料的是，CH还增加心肌梗塞的风险 中风的发生率从 40 岁开始增加，并且在 70 岁以上的人群中出现率超过 10%。 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之一。 与 CH 相关的 JAK2v617f (JAK2vf) 突变会增加 JAK/STAT 信号传导，从而导致 12 倍的增加 这些最近的观察强调了开发精确度的绝对必要性。 治疗这些患者的 CVD 的药物策略 我们已经报道了骨髓中携带 Jak2vf 突变的小鼠。 对小鼠的初步研究进一步表明，细胞表现出动脉粥样硬化和炎症小体激活的增加。 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。 采用混合骨髓移植模型，其中 20% 的骨髓细胞带有 Jak2vf 突变，并且 其余 80% 为野生型，在这些 Jak2vf-CH 小鼠中，Jak2vf 存在于约 25% 的 CD45+ 血细胞中，但在病变中。 Jak2vf 包含 50% 的 CD45+ 细胞，因此代表斑块内的克隆扩增。 我们将检验以下假设：在 CH 的 Jak2vf 模型中，炎症小体激活增加会导致 IL-1β 增加 促进 Mφ 增殖、细胞焦亡和动脉粥样硬化形成的分泌。 目标 1 将检验这一假设。 高胆固醇血症驱动的 Jak2vf-CH 模型中，施用 IL-1β 抗体将导致 Jak2vf Mφ 降低？ 此外，我们之前报道过 Jak2vf 小鼠具有增殖、Mφ? 积累较少和病变较小等特点。 坏死核心形成增加，最近我们发现 Caspase1/11 的缺失使坏死核心正常化 Jak2vf 小鼠中的区域，表明 GASDERMIN D 下游激活介导的细胞焦亡增加。因此， 具体目标 2 将通过饲养 Gsdmd-/- 小鼠来检查细胞焦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，该机制可能最终导致细胞焦亡成功。 完成拟议的研究将增强我们对驱动动脉粥样硬化增加的机制的理解 Jak2vf 介导的 CH 使用 IL-1β 抗体的研究可能为考虑使用这些疗法提供基础。 人类。