Mosaic loss of Y chromosome in blood and heart failure

血液中 Y 染色体马赛克丢失与心力衰竭

基本信息

批准号：
10277645
负责人：
KENNETH WALSH
金额：
$ 43.06万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10277645
关键词：
ATAC-seq Address Age Aging Biological Aging Biological Markers Blood Blood Cells CRISPR/Cas technology Cardiac Cardiometabolic Disease Cardiovascular Diseases Coculture Techniques Code DNA Sequence Alteration Data Disease Elderly Exhibits Fibroblasts Frequencies Genes Genomic Instability Heart Heart failure Hematologic Neoplasms Hematopoiesis Hematopoietic Neoplasms Histologic Human Hypertrophy Inflammation Knockout Mice Knowledge Light Link Longevity Modeling Mosaicism Mus Mutate Mutation Myocardial Myocardium Pathologic Pathology Phenotype Precancerous Conditions Procedures Process Proteins Recurrence Research Risk Role Sex Differences Signal Transduction Testing Therapeutic Transforming Growth Factor beta Woman Work Y Chromosome age related base cardioprotection cardiovascular risk factor chromosome Y loss constriction coronary fibrosis epidemiology study interest macrophage male men mortality mouse model novel premalignant pressure targeted treatment

项目摘要

SUMMARY Recent technological advances indicate that somatic DNA mutations accumulate with age and are remarkably prevalent. The accumulation of mutations in blood cells has been associated with increases in all-cause mortality and cardiometabolic diseases. Studies have focused on the precancerous clonal hematopoiesis state that results from mutations in “driver” genes that recurrently mutate in blood cancers. However, this class of mutations represent a small fraction of the total somatic mosaicism that occurs in blood. Mosaic loss of the Y chromosome (mLoY) in blood is the most common post-zygotic mutation in humans. Epidemiological studies have associated mLoY with all-cause mortality and a number of age-associated diseases. However, it is unknown whether there is a causal connection between mLoY and cardiovascular disease. Here, we will employ multiple murine models to assess the impact of mLoY in heart failure, and investigate this relationship at a mechanistic level.

概括最近的技术进步表明，体细胞 DNA 突变随着年龄的增长而积累，并且异常罕见。血细胞突变的积累与各种原因的增加有关。研究重点是癌前克隆造血状态。这是由在血癌中反复突变的“驱动”基因突变引起的。突变仅占血液中发生的体细胞嵌合性损失的一小部分。血液中的染色体（mLoY）是人类流行病学研究中最常见的合子后突变。 mLoY 与全因死亡率和许多与年龄相关的疾病有关。尚不清楚mLoY与心血管疾病之间是否存在因果关系。采用多个小鼠模型来评估 mLoY 对心力衰竭的影响，并研究这种关系在机械层面上。