Inflammatory contributions of clonal hematopoiesis to cardiovascular disease

克隆造血的炎症对心血管疾病的贡献

• 批准号: 10724237
• 负责人: Sarah S Burns
• 金额: $ 4.49万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724237
• 关键词: Acceleration; Adaptor Signaling Protein; Address; Age; Aging; Arterial Fatty Streak; Atherosclerosis; Blood Cells; Blood Platelets; Cardiovascular Diseases; Cardiovascular Manifestation; Cell Differentiation process; Cell Lineage; Cells; Clinical; Complex; Coronary heart disease; Development; Dioxygenases; Disease Progression; Epigenetic Process; Evaluation; Exhibits; Fellowship; Flow Cytometry; Genes; Genetic; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Immune; Individual; Inflammation; Inflammatory; Inflammatory Response; Innovative Therapy; Interleukin-1; Interleukin-1 beta; Interleukin-6; Investigation; Macrophage; Mediating; Medical; Monitor; Mus; Mutate; Mutation; Myelogenous; Myeloid Cells; Myocardial Infarction; Nature; Onset of illness; Pathogenesis; Pathology; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Play; Population; Preleukemia; Process; Receptor Signaling; Risk; Role; Signal Pathway; Signal Transduction; Somatic Mutation; T-Lymphocyte; Techniques; Tetanus Helper Peptide; Toll-like receptors; cardiovascular disorder risk; cell type; clinical care; cytokine; early onset; improved; innovation; leukemia; mast cell; monocyte; mortality; novel; novel therapeutics; pharmacologic; prevent; screening; single-cell RNA sequencing; targeted treatment; therapeutic development; therapeutic target; transcription factor; treatment response; ultrasound

PROJECT SUMMARY/ABSTRACT Clonal hematopoiesis of indeterminate potential (CHIP) is a common but poorly understood condition that predisposes asymptomatic individuals to leukemia and cardiovascular disease (CVD) and is associated with increased mortality. A recently-discovered condition, CHIP is characterized by the acquisition of age- associated somatic mutations that promote the expansion of specific blood cell populations, or clones, in a process called clonal hematopoiesis (CH). While CHIP-associated mutations, such as mutations in the epigenetic regulator Tet methylcytosine dioxygenase 2 (TET2), are frequently observed in leukemia, individuals with CHIP are at an even greater risk of CVD, including coronary heart disease and early-onset myocardial infarction, and the mechanisms underlying these cardiovascular manifestations are not well understood. While loss of Tet2 in hematopoietic cells accelerates atherosclerosis via the secretion of interleukin-1 (IL-1β) from pro-inflammatory macrophages, inhibition of IL-1 signaling only partially prevents atherosclerotic plaque formation, suggesting that additional inflammatory pathways contribute to this pathology. Indeed, our group has demonstrated that hyperactivation of toll-like receptor (TLR) signaling and downstream pro-inflammatory transcription factors promote CH and that a feedforward loop involving these pathways in hematopoietic stem and progenitor cells (HSPCs) propagates CH. However, it is not yet know if these pathways contribute to CHIP-associated CVD and if HSPCs play a direct role in this context. We hypothesize that the complex inflammatory response in Tet2-deficient CHIP-associated CVD relies on a pro-inflammatory feedforward loop between HSPCs and multiple mature hematopoietic lineages mediated by IL-1β, IL-6, and MYD88 signaling and that suppression of established CVD requires downstream inhibition of these pathways. To investigate this hypothesis, we propose the following specific aims: (1) to interrogate the inflammatory pathways underlying CHIP-associated CVD and (2) to investigate whether HSPCs and mature myeloid lineages contribute to a pro-inflammatory feedforward loop in CHIP-associated CVD. The objective of this fellowship is to determine the inflammatory signaling pathways and hematopoietic lineages underlying CHIP-associated CVD and to investigate their feasibility as therapeutic targets. To address these aims, genetic and pharmacologic approaches will be used to dissect the contributions of these pathways and cell types. Innovative techniques, including single cell-RNA sequencing, flow cytometry, and ultrasound, will be employed to elucidate the cell-type heterogeneity of CHIP and to monitor translationally-relevant indicators of disease progression and therapeutic response. The significance of this proposal is the identification of potential therapies for established CHIP-associated CVD. As patients with CHIP often present with established CVD, a better understanding of these pathways and the development of therapeutic agents that can effectively ameliorate established CVD would significantly improve the clinical care of these patients.

项目概要/摘要 不确定潜能克隆造血 (CHIP) 是一种常见但知之甚少的疾病， 使无症状个体易患白血病和心血管疾病 (CVD)，并与 CHIP 是一种最近发现的疾病，其特征是年龄增加。 相关的体细胞突变促进特定血细胞群或克隆的扩增 这个过程称为克隆造血（CH），而CHIP相关的突变，例如突变。 表观遗传调节剂 Tet 甲基胞嘧啶双加氧酶 2 (TET2) 经常在白血病中观察到， 患有 CHIP 的个体患 CVD 的风险更大，包括冠心病和早发性心脏病 心肌梗塞，以及这些心血管表现背后的机制尚不清楚 据了解，造血细胞中 Tet2 的缺失会通过分泌 来自促炎性巨噬细胞的白介素-1 (IL-1β)，抑制 IL-1 信号传导只能部分阻止 动脉粥样硬化斑块的形成，表明其他炎症途径有助于此 事实上，我们的团队已经证明 Toll 样受体 (TLR) 信号传导的过度激活和 下游促炎转录因子促进 CH，并且涉及这些因子的前馈循环 然而，目前尚不清楚造血干细胞和祖细胞 (HSPC) 是否会传播 CH。 这些途径会导致 CHIP 相关的 CVD，并且 HSPC 是否在这方面发挥直接作用。 我们认为，Tet2 缺陷的 CHIP 相关 CVD 中复杂的炎症反应依赖于 HSPC 和多个成熟造血谱系之间的促炎前馈环 IL-1β、IL-6 和 MYD88 信号传导以及抑制已建立的 CVD 需要下游抑制 为了研究这一假设，我们提出以下具体目标：（1）询问 CHIP 相关 CVD 的炎症通路以及 (2) 研究 HSPC 是否成熟 骨髓谱系有助于 CHIP 相关 CVD 的促炎前馈循环。 该奖学金旨在确定炎症信号传导途径和潜在的造血谱系 CHIP 相关的 CVD 并研究其作为治疗靶点的可行性。 药理学方法将用于剖析这些途径和细胞类型的贡献。 将采用创新技术，包括单细胞 RNA 测序、流式细胞术和超声波 阐明 CHIP 的细胞类型异质性并监测疾病的翻译相关指标 该提案的意义在于确定潜在的进展和治疗反应。 针对已确诊的 CHIP 相关 CVD 的治疗 由于 CHIP 患者经常出现已确诊的 CVD，因此 更好地了解这些途径以及开发能够有效治疗的药物 改善已确定的CVD将显着改善这些患者的临床护理。