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Transcriptomic signatures of menopause across human tissues

人体组织中更年期的转录组特征

基本信息

批准号：
10352100
负责人：
Elizabeth Theusch
金额：
$ 8.08万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10352100
关键词：
Adipose tissue Age Aging Biology Blood Pressure Blood Vessels Breast Cardiovascular Diseases Chronology Classification Conflict (Psychology)Coronary heart disease Data Data Set Detection Development Dimensions Endocrine Estrogens Evaluation Female Future Gene Expression Gene Expression Regulation Genes Genetic Transcription Genotype Gonadal Steroid Hormones Health Hormonal Hormonal Change Human Individual Knowledge Lead Lipids Liver Menopausal Status Menopause Methodology Molecular Obesity Ovarian Ovarian Follicle Pathway interactions Physiological Plasma Postmenopause Premenopause Process Regulation Research Risk Risk Factors Sampling Signal Transduction Stroke Supplementation Therapeutic Tissues Uterus Woman Women&apos s Health age effect aging gene base bone burden of illness cardiometabolism cardiovascular disorder risk cardiovascular health cell type differential expression disorder risk experience female sex hormone heart disease risk hormone therapy human tissue improved innovation insight male men mortality mortality risk negative affect novel therapeutics reproductive sex stroke risk transcriptomics treatment duration

项目摘要

SUMMARY An important aging milestone for women is menopause. Unfortunately, postmenopausal women have increased coronary heart disease, stroke, and mortality risk after menopause. This can be partially attributed to increases in cardiovascular disease (CVD) risk factors that many women experience after menopause, such as blood pressure, lipid levels, and adiposity, but the mechanisms behind these and other changes are poorly understood. A reduction in circulating estrogen levels is one of the major changes with menopause, and estrogen can transcriptionally regulate many genes, often in a tissue-specific manner. Prior studies of changes in gene expression with menopause have been limited, and most have been focused on breast, bone, and female reproductive tissues. We hypothesize that transcriptomic examination of cardiometabolic tissues across the menopause transition will reveal insight into the molecular processes responsible for the increased CVD risk. Though menopause status information is missing from most human tissue gene expression datasets, we hypothesize that menopausal status can be inferred from gene expression data. To accomplish this, in Aim 1A we will infer the menopausal status of hundreds of female Genotype-Tisssue Expression (GTEx) subjects based on the gene expression profiles of their female reproductive tissues, using a combination of dimensionality reduction approaches informed by known biology and more agnostic, clustering-based methodology. Since the average GTEx subject contributed samples from over 18 tissues, we will have inferred menopausal status information for non-reproductive tissues as well. In a preliminary analysis of uterus gene expression data (withholding age as a covariate), we observed clear classification of individuals into an inferred premenopausal (age<54) and an inferred postmenopausal group (age>48). Since menopause status is confounded by age, in Aim 1B we will identify sex-specific aging genes and examine the relationship of gene expression with chronological age in each sex subset. In Aim 1C, we will use the inferred menopausal status information from Aim 1A to identify genes and pathways that are differentially expressed in tissues derived from inferred premenopausal versus postmenopausal women, focusing on cardiometabolic tissues of relevance to cardiovascular disease, such as liver, adipose, and blood vessels. Inferred menopause-related genes that do not exhibit similar correlations with chronological age in male tissues are likely to be regulated by the female- specific hormonal changes during menopause rather than more general aging processes. Overall, this will be the most comprehensive evaluation of the effects of menopause on gene expression performed to date, and the findings could identify molecular pathways underlying the increased disease burden in post-menopausal women.

总结