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

基本信息

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
项目类别：
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

项目摘要

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，体细胞突变在癌症以外的与年龄相关的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仍然很大程度上尚未被探索。最近的大型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频率的增加有关。造血系统，为突变细胞提供竞争性生长优势，从而使其能够克隆扩张（体细胞突变驱动的克隆造血）。我们最近的研究支持了这一观点 Science（Fuster 等人，Science 2017）证明，造血细胞的克隆扩增缺乏 TET2 是老年人血细胞中最常见的突变基因之一，加速了高脂血症小鼠的动脉粥样硬化斑块形成（动脉粥样硬化）。虽然这项研究提供了因果关系和机制见解的实验证据支持血细胞中的体细胞突变动脉粥样硬化性心血管疾病的新贡献者，推断这些结果存在局限性到临床场景。具体来说，在我们的实验研究中，克隆性造血先于动脉粥样硬化斑块诱导；然而，临床研究表明，大量的亚临床动脉粥样硬化已经存在大多数个体的年龄通常早于体细胞突变驱动的克隆的发展造血作用。此外，越来越多的人接受预防性治疗降胆固醇药物，但克隆造血对由以下药物引起的斑块停滞/消退的影响降低血液胆固醇仍然完全未被探索。基于这些临床事实，总体该提案的目的是研究体细胞 TET2 突变驱动的克隆造血是否影响动脉粥样硬化在动脉粥样硬化斑块进展或停滞/消退的临床相关环境中。目的 1将评估TET2缺陷型造血细胞克隆扩增对动脉粥样硬化的影响高脂血症小鼠的斑块进展以及血液胆固醇诱导的斑块停滞/消退降低。目标 2 将剖析 TET2 突变对斑块影响的分子机制重塑。目标 3 将探讨针对下游机械节点的干预措施的假设造血系统 TET2 缺陷可预防小鼠动脉粥样硬化加速 TET2 功能驱动的克隆造血功能丧失。