Transcriptomic signatures of menopause across human tissues

人体组织中更年期的转录组特征

• 批准号: 10581155
• 负责人: Elizabeth Theusch
• 金额: $ 12.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581155
• 关键词: Adipose tissue; Adult; Age; Aging; Biology; Blood Pressure; Blood Vessels; Breast; Cardiovascular Diseases; Chronology; Classification; 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; Lipids; Liver; Menopausal Status; Menopause; Methodology; Molecular; Obesity; Ovarian; Ovarian Follicle; Pathway interactions; Perimenopause; Physiological; Plasma; Postmenopause; Premenopause; Process; Regulation; Research; Risk; Risk Factors; Sampling; Signal Transduction; Stroke; Supplementation; Therapeutic; Tissues; Uterus; Woman; Women' s Health; age effect; aging gene; bone; burden of illness; cardiometabolism; cardiovascular disorder risk; cardiovascular health; cell type; differential expression; disorder risk; experience; female sex hormone; gene interaction; heart disease risk; hormone therapy; human tissue; improved; innovation; insight; male; men; mortality; mortality risk; negative affect; novel therapeutics; reproductive; secondary analysis; sex; steroid hormone; stroke risk; transcriptomics; treatment duration

PROJECT SUMMARY Unfortunately, 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 and an inferred postmenopausal group. In Aim 1B, 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. Finally, since menopause status is confounded by age, in Aim 2 we will identify sex-specific aging genes in cardiometabolic GTEx tissues and other existing human tissue gene expression datasets with age and sex information from suitable numbers of younger (age<50) and older (age >50) adults and examine the relationship of gene expression with chronological age in each sex subset. 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.

项目摘要 不幸的是，女性在绝经后患冠心病、中风和死亡的风险增加。这 可部分归因于许多女性经历的心血管疾病（CVD）风险因素的增加 绝经后，如血压，血脂水平和肥胖，但这些背后的机制， 其他变化则知之甚少。循环中雌激素水平的降低是 雌激素可以转录调节许多基因，通常以组织特异性方式。之前 关于绝经后基因表达变化的研究有限，大多数研究集中在 乳房、骨骼和女性生殖组织。我们假设转录组学检查 在绝经过渡期的心脏代谢组织将揭示深入了解分子过程 导致CVD风险增加。虽然大多数人的更年期状态信息是缺失的， 组织基因表达数据集，我们假设绝经状态可以从基因表达推断， 数据为了实现这一点，在目标1A中，我们将推断数百名女性基因型-组织的绝经状态。 表达（GTEx）受试者的基础上，他们的女性生殖组织的基因表达谱，使用 结合已知的生物学和更不可知的降维方法，聚类- 基于方法论。由于GTEx受试者平均贡献了来自超过18种组织的样本，因此我们将获得 还可以推断非生殖组织的更年期状态信息。在对子宫的初步分析中 基因表达数据（保留年龄作为协变量），我们观察到个体明确分类为 推断绝经前和推断绝经后组。在目标1B中，我们将使用推断的绝经期 目的1A的状态信息，以鉴定在来源于 根据推断的绝经前与绝经后女性，重点关注相关的心脏代谢组织 心血管疾病，如肝脏，脂肪和血管。最后，由于更年期状态是 在目标2中，我们将在心脏代谢GTEx组织和其他组织中鉴定性别特异性衰老基因。 现有的人类组织基因表达数据集，其中包含来自适当数量的年轻人的年龄和性别信息， (age<50岁）和老年人（年龄>50岁），并检查基因表达与实际年龄的关系， 每个性别子集。推断的绝经相关基因，与时间无关， 男性组织中的年龄可能受绝经期女性特定激素变化的调节， 比一般的衰老过程更快。总的来说，这将是对 绝经期对基因表达的影响，研究结果可以确定分子途径 这是绝经后妇女疾病负担增加的根本原因。