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，非常明显流行。血细胞中突变的积累与全因的增加有关死亡率和心脏代谢疾病。研究重点是癌前的克隆造血状态这是由于“驱动器”基因突变在血液癌中反复突变的突变。但是，这类突变是血液中总细胞镶嵌物的一小部分。 Y 血液中的染色体（MLOY）是人类中最常见的杂化后突变。流行病学研究已将MLOY与全因死亡率和许多与年龄相关的疾病相关联。但是，是未知MLOY和心血管疾病之间是否存在因果关系。在这里，我们会的员工多种鼠模型来评估MLOY在心力衰竭中的影响，并调查这种关系在机械级别。