Somatic TET2 mutation-driven clonal hematopoiesis in atherosclerosis

摘要 随着时间的推移，体细胞DNA突变的积累是许多组织衰老的标志。但 体细胞突变在除癌症以外的年龄相关疾病中的因果作用是一个有争议的问题， 在心血管疾病的情况下仍然很大程度上未被探索。最近的大外显子组测序研究 人类已经表明，衰老不可避免地与增加的体细胞突变频率有关， 造血系统，其为突变细胞提供竞争性生长优势，从而允许其 克隆扩增（体细胞突变驱动的克隆造血）。支持这一观点，我们最近的研究， Science（Fuster et al，Science 2017）证明，造血细胞的克隆扩增在造血干细胞中缺乏。 TET 2是老年人血细胞中最常突变的基因之一， 动脉粥样硬化斑块形成（动脉粥样硬化形成）。虽然这项研究提供了 因果关系和机械见解的实验证据支持血细胞中的体细胞突变是 动脉粥样硬化性心血管疾病的新贡献者，在推断这些结果时存在局限性 到临床上。具体来说，在我们的实验研究中， 斑块诱导;然而，临床研究表明已经存在大量亚临床动脉粥样硬化 在大多数个体中，通常在体细胞突变发展之前的年龄， 造血此外，越来越多的人接受了 降低胆固醇的药物，但克隆造血的影响，在斑块停滞/消退诱导 降低血胆固醇仍然完全未被探索。基于这些临床事实， 本提案的目的是研究体细胞TET 2突变驱动的克隆造血是否影响 在动脉粥样硬化斑块进展或停滞/消退的临床相关环境中的动脉粥样硬化。目的 1将评估TET 2缺陷造血细胞克隆扩增在动脉粥样硬化中的作用。 高脂血症小鼠中的斑块进展和血液胆固醇诱导的斑块停滞/消退 降低。目的2将剖析TET 2突变在斑块中作用的分子机制 重塑目标3将探讨针对下游机制节点的干预措施的假设 造血系统中TET 2缺陷的小鼠可防止加速动脉粥样硬化， TET 2功能驱动的克隆造血功能丧失。

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.