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.

项目摘要 尽管LDL降低治疗成功，但动脉粥样硬化心血管疾病仍然是主要原因 在美国的死亡。使用抗炎疗法的最新临床试验显示CVD减少了 但导致感染增加。这表明迫切需要更精确地靶向抗炎 对炎症风险较高的患者的治疗。克隆造血（CH）来自体细胞突变 例如在JAK2或TET2中，为造血干细胞和克隆的生长提供了适应性优势 血细胞。 CH随着衰老而增加的频率，已成为主要的独立风险因素 CVD。 TET2 - / - 和JAK2VF小鼠模型的研究表明巨噬细胞炎症体的核心作用 激活。我们已经表明，动脉粥样硬化增加，肿瘤病缺陷，坏死增加和 在造血细胞和CH模型中表达JAK2VF的小鼠的炎性髓样细胞群体。 抑制炎性体产物LL-1β改善了斑块稳定的特征，包括增加 纤维帽和改善的坏死核。我们建议研究连接CH的机制 LL-1β下游作用于动脉粥样硬化斑块稳定性的炎症和途径。低频 JAK2VF等位基因在3-4％的一般人群中发现并增加CVD风险。我们最近的发现表明 仅移植1.5％JAK2VF细胞会导致病变增加，而肿瘤病的受损并增加 坏死。这表明了一个新的假设，即炎症性串扰从jak2vfμs到旁观者wtμφs或 基质细胞，促进牙菌斑不稳定。在AIM 1中，我们将评估CH对旁观者细胞的影响 关注JAK2VF -WTμφ串扰的病变。我们将评估以下假设 JAK2VF至WT巨噬细胞（例如炎性体源性IL-1）增加了炎症性巨噬细胞和 减少trem2Hi非炎性巨噬细胞，导致肿瘤病受损并炎症增加 在低等位基因负担JAK2VF CH的老鼠中。在AIM2中，我们将评估CH对JAK2VF或 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 动脉粥样硬化病变。我们还将采用一种新型的DRE-CRE鼠标模型，该模型允许JAK2VF灭活 在病变回归期间，以检验以下假设：这会增加纤维型Trem2Hi巨噬细胞和 病变盖中的成纤维细胞。在AIM 3中，我们将与慕尼黑血管生物库合作评估影响 CH上的人颈椎斑块炎症。提出的研究可能揭示了新型基因和途径作用 克隆造血的炎性体激活下游以破坏斑块，并指向新的斑块 与全球抑制IL-1β相比，更精确的靶向治疗方法不太免疫抑制作用 或炎症。