Clonal hematopoiesis and accelerated metabolic dysfunction in obesity

肥胖症中的克隆造血和加速代谢功能障碍

基本信息

批准号：
10390471
负责人：
KENNETH WALSH
金额：
$ 53.48万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10390471
关键词：
Adipose tissue Adoptive Transfer Adult Age Aging American Biological Assay Blood Vessels Bone Marrow Bone Marrow Cells Bone Marrow Transplantation Calories Cardiometabolic Disease Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Cell physiology Cells Censuses Cessation of life Chronic Disease Clonal Expansion DNA Sequence Alteration Data Diabetes Mellitus Diet Disease Elderly Epigenetic Process Event Exhibits Frequencies Functional disorder Genes Growth Health Hematopoiesis Hematopoietic Hematopoietic System Human Immune Individual Inflammasome Inflammation Inflammatory Insulin Resistance Interleukin-1 beta Leukocytes Link Malignant Neoplasms Mediating Metabolic Metabolic Diseases Metabolic dysfunction Modeling Molecular Mosaicism Mus Mutate Mutation Myelogenous Myeloid Cells Obesity Pancreas Pre-Clinical Model Process Property Research Role Sequence Analysis Signal Transduction Somatic Mutation Technology Testing Time Tissues Variant base cell age cytokine diabetes risk exome exome sequencing inhibitor loss of function macrophage mutant neutralizing antibody pre-clinical 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 unexplored in the setting of metabolic 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 (clonal hematopoiesis). Unexpectedly, these somatic mutations were associated with a higher rates of cardio-metabolic disease, suggesting a previously unrecognized link between somatic mutations in bone marrow-derived cells and these disease processes. However, whether there is a causal connection between these somatic mutations and metabolic dysfunction remains unclear and the potential underlying mechanisms are unknown, and this is the scientific premise of the proposed research.

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，并且在代谢疾病的背景下仍有待探索。最近的人类大型外显子组测序研究研究表明，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，从而使其克隆扩增（克隆造血）。出乎意料的是，这些体细胞突变与心脏代谢疾病的发病率较高，这表明以前未认识到躯体代谢疾病之间存在联系骨髓来源细胞的突变和这些疾病过程。然而，是否有一个这些体细胞突变与代谢功能障碍之间的因果关系仍不清楚，潜在的潜在机制尚不清楚，这是本研究的科学前提。