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。然而， 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， 在心血管疾病的背景下，很大程度上仍未被探索。最新的大外显子组测序研究 人类已经证明，衰老不可避免地与体细胞突变的频率增加有关 造血系统，它为突变细胞提供竞争生长优势，从而允许其 克隆性扩增(体细胞突变驱动的克隆性造血)。支持这一观点的是，我们最近在 《科学》(Fuster等人，《科学》2017)证明，在 TET2是老年人血细胞中最常见的突变基因之一，它加速了 高脂血症小鼠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 支持血细胞体细胞突变的因果关系和机制洞察力的实验证据 作为动脉粥样硬化性心血管疾病的新因素，推断这些结果存在局限性。 到临床场景中。具体地说，在我们的实验研究中，克隆造血先于动脉粥样硬化。 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，通常在体细胞突变驱动克隆发展之前的年龄 造血术。此外，越来越多的人接受预防性治疗。 降胆固醇药物，但克隆性造血对斑块停滞/消退的影响 降低血液中的胆固醇仍然是完全未被探索的。基于这些临床事实，最主要的 这项建议的目的是调查体细胞TET2突变驱动的克隆性造血是否影响 在动脉粥样硬化斑块进展或停止/消退的临床相关环境中的动脉粥样硬化。目标 1将评估TET2缺陷的造血细胞克隆性扩增在动脉粥样硬化中的作用 高脂血症小鼠斑块进展及血胆固醇诱导的斑块停滞/消退 放低。目的2将剖析斑块中TET2突变影响的分子机制 改建。目标3将探索以下假设：针对下游机械结点的干预 造血系统中TET2缺乏对表现为动脉粥样硬化加速的小鼠的保护作用 TET2功能缺失驱动的克隆性造血。

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.