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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：
10646348
负责人：
KENNETH WALSH
金额：
$ 45.11万
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/10646348
关键词：
ATAC-seq Ablation 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 Infiltration Inflammation Knockout Mice Knowledge Light Link Longevity Macrophage Modeling Mosaicism Mus Mutate Mutation Myocardial Myocardium Pathologic Pathology Phenotype Precancerous Conditions Procedures Process Proteins Recurrence Research Risk Role Sex Differences Signal Transduction Technology Testing Therapeutic Transforming Growth Factor beta Woman Work Y Chromosome age related aorta constriction cardioprotection cardiovascular risk factor chromosome Y loss coronary fibrosis epidemiology study interest male men mortality mosaic loss 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.

摘要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，并显著很流行。血细胞突变的积累与全因致病的增加有关。死亡率和心脏代谢性疾病。研究集中在癌前状态的克隆性造血。这是由于“驱动”基因的突变导致了血癌的反复突变。然而，这一类的突变只占血液中发生的全部体细胞嵌合体的一小部分。Y的马赛克损失血液中的染色体(MLoY)是人类最常见的合子后突变。流行病学研究将mLoY与全因死亡和一些与年龄相关的疾病联系起来。然而，它是尚不清楚mLoY与心血管疾病之间是否存在因果联系。在这里，我们将使用多个小鼠模型评估mLoY在心力衰竭中的影响，并研究这种关系在机械论层面上。