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Hematopoietic stem cell mutations and ischemic cardio-metabolic disease

造血干细胞突变与缺血性心脏代谢疾病

基本信息

批准号：
10161815
负责人：
KENNETH WALSH
金额：
$ 48.5万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161815
关键词：
Adult Age Aging Angiotensin II Atherosclerosis Blood Cells Bone Marrow Candidate Disease Gene Cardiac Cardiometabolic Disease Cardiovascular Diseases Cardiovascular Pathology Cardiovascular system Cause of Death Cell Lineage Cell physiology Cells Cessation of life Characteristics Clinical Clonal Expansion Clonal Hematopoietic Stem Cell Clustered Regularly Interspaced Short Palindromic Repeats Cytokine Gene DNA Sequence Alteration Data Disease Disease model Dissection Elderly Epigenetic Process Evaluation Fibrosis Frequencies Gene Expression Genes Gold Growth Heart Heart failure Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Human Hypertension Hypertrophy Immune In Vitro Individual Inflammation Infusion procedures Interleukin-1 beta Ischemia Lentivirus Lentivirus Vector Link Malignant Neoplasms Modeling Mosaicism Mutate Mutation Outcome Pathologic Pathologic Processes Pattern Pharmacology Phenotype Play Population Process Protocols documentation Publishing Reporting Reproducibility Research Role Somatic Mutation Stress Surgical Models Testing Time Tissues Validation cardiometabolism clinically significant cytokine driver mutation epidemiology study exome sequencing expression cloning hematopoietic stem cell expansion immunoregulation kidney dysfunction mortality mutant overexpression premalignant response

项目摘要

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.

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。