Somatic TET2 mutation-driven clonal hematopoiesis in atherosclerosis

动脉粥样硬化中体细胞 TET2 突变驱动的克隆造血

• 批准号: 9913594
• 负责人: Coleen A McNamara
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913594
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Affect; Age; Aging; Arterial Fatty Streak; Atherosclerosis; Blood; Blood Cells; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cause of Death; Cells; Cessation of life; Cholesterol; Clinical; Clinical Research; Clonal Expansion; DNA Sequence Alteration; Development; Disease; Elderly; Ensure; Etiology; Exhibits; Frequencies; Functional disorder; Future; Genes; Growth; Hematopoiesis; Hematopoietic; Hematopoietic System; Hepatic; Human; Incidence; Individual; Interleukin-1 beta; Intervention; Investigation; Link; Malignant Neoplasms; Mediating; Methodology; Modeling; Molecular; Mus; Mutate; Mutation; Nature; Nodal; Pharmaceutical Preparations; Pharmacology; Pre-Clinical Model; Preclinical Testing; Preventive care; Research; Role; Science; Somatic Mutation; Systems Development; Testing; Time; Tissues; Virus; age related; atherogenesis; base; clinically relevant; exome sequencing; experimental study; in vivo; insight; loss of function; macrophage; mouse model; mutant; personalized medicine; prevent; prophylactic; targeted treatment

ABSTRACT The accumulation of somatic DNA mutations over time is a hallmark of aging in many tissues. However, the causal role of somatic mutations in age-associated disorders other than cancer is a matter of debate and remains largely unexplored in the setting of cardiovascular disease. Recent large exome sequencing studies in humans have shown that aging is inevitably associated with an increased frequency of somatic mutations in the hematopoietic system, which provide a competitive growth advantage to the mutant cell and thus allow its clonal expansion (somatic mutation-driven clonal hematopoiesis). Supporting this notion, our recent study in Science (Fuster et al, Science 2017) demonstrated that the clonal expansion of hematopoietic cells deficient in TET2, one of the most frequently mutated genes in blood cells of elderly individuals, accelerates atherosclerotic plaque formation (atherogenesis) in hyperlipidemic mice. While this study provided experimental evidence of causality and mechanistic insight supporting that somatic mutations in blood cells are a new contributor to atherosclerotic cardiovascular disease, there are limitations in extrapolating these results to the clinical scenario. Specifically, in our experimental study, clonal hematopoiesis preceded atherosclerotic plaque induction; however, clinical studies show that substantial subclinical atherosclerosis is already present in most individuals at ages that typically precede the development of somatic mutation driven-clonal hematopoiesis. Furthermore, an increasing percentage of individuals are prophylactically treated with cholesterol-lowering drugs, but the impact of clonal hematopoiesis in plaque arrest/regression induced by blood cholesterol lowering remains completely unexplored. Based on these clinical facts, the overarching objective of this proposal is to investigate whether somatic TET2 mutation-driven clonal hematopoiesis affects atherosclerosis in the clinically relevant settings of atherosclerotic plaque progression or arrest/regression. Aim 1 will evaluate the effects of the clonal expansion of TET2-deficient hematopoietic cells in atherosclerotic plaque progression in hyperlipidemic mice and in plaque arrest/regression induced by blood cholesterol lowering. Aim 2 will dissect the molecular mechanisms underlying the effects of TET2 mutations in plaque remodeling. Aim 3 will explore the hypothesis that interventions targeting mechanistic nodal points downstream of TET2 deficiency in the hematopoietic system protect against accelerated atherosclerosis in mice exhibiting TET2 loss of function-driven clonal hematopoiesis.

抽象的 随着时间的流逝，体细胞DNA突变的积累是许多组织衰老的标志。但是， 体细胞突变在癌症以外的其他年龄相关疾病中的因果作用是一个争论和 在心血管疾病的情况下，仍未探索。最近的大型外显子组测序研究 人类已经表明，衰老不可避免地与体细胞突变的频率增加有关 造血系统，为突变细胞提供了竞争增长优势，因此允许其 克隆膨胀（体突变驱动的克隆造血）。支持这个概念，我们最近的研究 科学（Fuster等，Science 2017）表明，造血细胞的克隆扩张不足 TET2是老年人血细胞中最常见的突变基因之一，加速了 高脂小鼠的动脉粥样硬化斑块形成（动脉粥样硬化）。这项研究提供了 因果关系和机械洞察的实验证据，证明血细胞中的体细胞突变是 动脉粥样硬化心血管疾病的新贡献者，推断这些结果存在局限性 到临床情况。具体而言，在我们的实验研究中，克隆造血作用先于动脉粥样硬化 斑块诱导；但是，临床研究表明，已经存在大量亚临床动脉粥样硬化 在大多数年龄段的人，通常是在躯体突变驱动 - 连锁的发展之前 造血。此外，对个人的比例越来越多。 降低胆固醇的药物，但克隆造血作用在由斑块停滞/回归中的影响 降低血液胆固醇仍然完全没有探索。基于这些临床事实，总体 该建议的目的是研究体细胞TET2突变驱动的克隆造血作用是否影响 动脉粥样硬化的动脉粥样硬化环境中的动脉粥样硬化进展或停滞/消退。目的 1将评估动脉粥样硬化中TET2缺陷型造血细胞克隆膨胀的影响 高脂小鼠的斑块进展以及血液胆固醇诱导的斑块停滞/回归中的进展 降低。 AIM 2将剖析斑块中TET2突变作用的分子机制 重塑。 AIM 3将探讨以下假设：针对下游机理节点点的干预措施 造血系统中TET2缺乏症可以防止出现的小鼠加速动脉粥样硬化 TET2功能驱动的克隆造血的丧失。