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

• 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
• 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

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.

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