Hematopoietic stem cell mutations and ischemic cardio-metabolic disease

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。 心血管疾病(CVD)是老年人死亡的主要原因，在这一背景下仍未得到探索 个人。最近对人类的大型外显子组测序研究表明，衰老不可避免地与 随着造血系统中体细胞突变频率的增加，这提供了一个具有竞争力的 对突变细胞的生长有利，从而允许其克隆性扩增(克隆性造血)。出乎意料的是， 这些体细胞突变与较高的心血管相关死亡率有关， 提示骨髓来源细胞的体细胞突变之间存在以前未被发现的联系 和心血管疾病。最近，我们报道了发生在造血干细胞中的TET2癌前驱动突变 细胞可能与心血管疾病有因果关系。然而，是否存在因果关系 其他克隆性造血基因与心血管疾病之间的关系尚不清楚 机制是完全未知的；这是拟议研究的科学前提。在这里，我们将 使用慢病毒/CRISPR基因编辑方法来操纵其他造血干细胞驱动基因和 在心脏代谢疾病的多方面模型中评估它们的影响。

SUMMARY 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 unexplored in the setting of cardiovascular disease (CVD), the leading cause of death in elderly individuals. 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 (clonal hematopoiesis). Unexpectedly, these somatic mutations were associated with a higher rate of cardiovascular-related deaths, suggesting a previously unrecognized link between somatic mutations in bone marrow-derived cells and CVD. Recently, we reported that pre-cancerous driver mutations in Tet2 that occur in hematopoietic stem cells may be causally linked to cardiovascular disease. However, whether there is a causal connection between other clonal hematopoiesis genes and CVD remains unclear and the potential underlying mechanisms are completely unknown; and this is the scientific premise of the proposed research. Here, we will use a lentivirus/CRISPR gene editing approach to manipulate other hematopoietic stem cell driver genes and assess their impacts in a multi-faceted model of cardio-metabolic disease.