New therapeutic approaches in clonal hematopoiesis and atherosclerosis

克隆造血和动脉粥样硬化的新治疗方法

• 批准号: 10719058
• 负责人: ALAN richard TALL
• 金额: $ 69.47万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719058
• 关键词: Acceleration; Age; Aging; Alleles; Anti-Inflammatory Agents; Antibodies; Arterial Fatty Streak; Atherosclerosis; Blood Cells; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Carotid Artery Plaques; Cause of Death; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clinical; Clinical Trials; Collaborations; Cytokine Signaling; Epigenetic Process; Fibroblasts; Frequencies; General Population; Genes; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Immune; Immunosuppression; Impairment; Infection; Inflammasome; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 beta; JAK2 gene; Lesion; Link; Low-Density Lipoproteins; Macrophage; Maps; Mediating; Mesenchymal Stem Cells; Modeling; Modification; Mus; Mutation; Myeloid Cells; Myocardial Infarction; Necrosis; Observational Study; Outcome; Pathway interactions; Patients; Population; Precision therapeutics; Resolution; Risk; Risk Factors; Role; Signal Transduction; Somatic Mutation; Stromal Cells; TREM2 gene; Techniques; Testing; Therapeutic Intervention; Thick; Transplantation; Variant; Visualization; antagonist; atherosclerosis risk; biobank; cardiovascular disorder risk; cardiovascular risk factor; fitness; hematopoietic gene; improved; insight; mouse model; mutant; novel; novel therapeutic intervention; premature; stem; success; targeted treatment; transcriptome sequencing; translational study

PROJECT SUMMARY Despite the success of LDL lowering treatments, atherosclerotic cardiovascular disease remains the major cause of death in the US. Recent clinical trials employing anti-inflammatory therapies have shown a reduction in CVD but led to increased infections. This indicates an urgent need for more precise targeting of anti-inflammatory treatments to patients with higher inflammatory risk. Clonal hematopoiesis (CH) arises from somatic mutations such as in JAK2 or TET2 that provide a fitness advantage to hematopoietic stem cells and outgrowth of clones of blood cells. CH, which increases in frequency with aging, has emerged as a major independent risk factor for CVD. Studies in Tet2-/- and Jak2VF mouse models indicate a central role of macrophage inflammasome activation. We have shown increased atherosclerosis, defective efferocytosis, increased necrosis and inflammatory myeloid cell populations in mice expressing Jak2VF in hematopoietic cells and in CH models. Inhibition of the inflammasome product lL-1β improved features of plaques stabilization including increased fibrous caps and decreased necrotic cores. We propose to investigate the mechanisms linking CH, inflammasomes and pathways acting downstream of lL-1β to atherosclerotic plaque stability. Low frequency Jak2VF alleles are found in 3-4% of general populations and increase CVD risk. Our recent findings indicate that transplantation of only 1.5% Jak2VF cells leads to increased lesions with impaired efferocytosis and increased necrosis. This suggests a new hypothesis that inflammatory crosstalk from Jak2VF Μφs to bystander WT Μφs or stromal cells, promotes plaque destabilization. In Aim 1 we will assess the impact of CH on bystander cells in lesions focusing on Jak2VF -WT Μφ crosstalk. We will evaluate the hypothesis that inflammatory signals from Jak2VF to WT macrophages, such as inflammasome-derived IL-1, increase inflammatory macrophages and decrease Trem2Hi non-inflammatory macrophages, leading to impaired efferocytosis and increased inflammation in mice with low allele burden Jak2VF CH. In Aim2 we will assess the impact of CH on stromal cells in Jak2VF or Tet2-/- CH mice, building on preliminary studies showing that IL-1b antagonism increases fibroblasts in the cap of atherosclerotic lesions. We will also employ a novel Dre-Cre mouse model that allows Jak2VF to be inactivated during lesion regression to test the hypothesis that this increases fibrogenic Trem2Hi macrophages and fibroblasts in lesion caps. In Aim 3 we will collaborate with the Munich Vascular Biobank to assess the impact of CH on human carotid plaque inflammation. Proposed studies may reveal novel genes and pathways acting downstream of inflammasome activation in clonal hematopoiesis to destabilize plaques, and point to new and more precisely targeted therapeutic approaches that are less immunosuppressive than global inhibition of IL-1β or inflammasomes.

项目概要 尽管降低低密度脂蛋白的治疗取得了成功，但动脉粥样硬化性心血管疾病仍然是主要原因 在美国的死亡。最近采用抗炎疗法的临床试验表明心血管疾病的发生率有所降低 但导致感染人数增加。这表明迫切需要更精确的抗炎靶向药物 对炎症风险较高的患者进行治疗。克隆造血（CH）源自体细胞突变 例如 JAK2 或 TET2 为造血干细胞和克隆的生长提供适应性优势 血细胞。 CH 的发生频率随着年龄的增长而增加，已成为一种主要的独立危险因素 化学气相沉积。 Tet2-/- 和 Jak2VF 小鼠模型的研究表明巨噬细胞炎性体的核心作用 激活。我们已经发现动脉粥样硬化增加、胞吞作用缺陷、坏死增加和 在造血细胞和 CH 模型中表达 Jak2VF 的小鼠中炎症性骨髓细胞群。 抑制炎症体产物 lL-1β 可改善斑块稳定的特征，包括增加 纤维帽和坏死核减少。我们建议研究 CH 之间的联系机制， 炎症小体和作用于 lL-1β 下游的通路对动脉粥样硬化斑块的稳定性。低频 Jak2VF 等位基因存在于 3-4% 的普通人群中，会增加 CVD 风险。我们最近的研究结果表明 仅移植 1.5% Jak2VF 细胞会导致病变增加，胞吞作用受损，并增加 坏死。这提出了一个新的假设，即从 Jak2VF Mφs 到旁观者 WT Mφs 的炎症串扰或 基质细胞，促进斑块不稳定。在目标 1 中，我们将评估 CH 对旁观者细胞的影响 病变集中于 Jak2VF -WT Mφ 串扰。我们将评估以下假设：炎症信号来自 Jak2VF 与 WT 巨噬细胞（例如炎症小体衍生的 IL-1）相比，会增加炎症巨噬细胞的数量， 减少 Trem2Hi 非炎症巨噬细胞，导致胞吞作用受损和炎症增加 在具有低等位基因负荷 Jak2VF CH 的小鼠中。在 Aim2 中，我们将评估 CH 对 Jak2VF 或 Jak2VF 中基质细胞的影响 Tet2-/- CH 小鼠，基于初步研究表明 IL-1b 拮抗作用会增加帽中的成纤维细胞 的动脉粥样硬化病变。我们还将采用一种新型 Dre-Cre 小鼠模型，使 Jak2VF 失活 在病变消退过程中测试这一假设，即这会增加纤维化的 Trem2Hi 巨噬细胞和 病变帽中的成纤维细胞。在目标 3 中，我们将与慕尼黑血管生物库合作评估影响 CH 对人颈动脉斑块炎症的影响。拟议的研究可能揭示新的基因和途径 克隆造血过程中炎症小体激活的下游，破坏斑块的稳定，并指出新的和 更精确的靶向治疗方法，其免疫抑制程度低于 IL-1β 的整体抑制 或炎症小体。