Regulatory Landscape of the Aging Human Ovary

人类卵巢衰老的调控景观

• 批准号: 10441547
• 负责人: MICHAEL G ROSENFELD
• 金额: $ 33.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441547
• 关键词: Affect; Age; Aging; Attention; Biological Assay; Birth; Cardiovascular Diseases; Cell model; Cells; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Coupled; Development; Disease; Elderly; Engineering; Enhancers; Exhibits; Feedback; Female; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic Variation; Genomics; Growth; Health; Homeostasis; Human; Human body; Individual; Inflammatory; Licensing; Life Expectancy; Link; Longevity; Menopause; Messenger RNA; Metabolic syndrome; Methodology; Modeling; Molecular; Mus; Neurodegenerative Disorders; Nuclear RNA; Oocytes; Organ; Outcome; Ovarian; Ovarian aging; Ovary; Pathologic; Postmenopause; Preparation; Proxy; Regulator Genes; Reproductive Periods; Reproductive Process; Risk; Role; Signal Transduction; Supporting Cell; Surveys; Technology; Time; Transcriptional Regulation; Transplantation; Transposase; Trees; Variant; Woman; body system; cancer type; causal variant; cell type; gene regulatory network; genetic variant; genome wide association study; genomic data; granulosa cell; healthspan; human embryonic stem cell; improved; in silico; insight; interdisciplinary approach; mouse model; programs; reproductive senescence; single cell technology; single-cell RNA sequencing; transcription factor; transcriptome sequencing; trustworthiness

Reproductive aging is a major health, personal and societal issue, but ovarian aging has received limited scientific attention, even in large genomic survey projects. Ovarian aging influences diverse health outcomes in women including lifespan, cardiovascular disease, metabolic syndromes, neurodegenerative disorders and various types of cancer. Yet the molecular mechanisms underlying ovarian aging, timing of menopause and inter-organ feedback loops remain elusive. As one of the most dynamic organs in the human body, the ovary undergoes significant remodeling across the entire reproductive period. The dynamic transcriptional regulation of and interactions between oocytes and their surrounding cells during aging remain unknown. The objective of this proposal is to understand the regulatory landscapes underlying the complex interplay among the different cell types in the ovary and to investigate the molecular mechanisms that regulate the remarkably complex processes of reproductive aging. We will apply powerful single-cell (sc) RNA-seq and scATAC-seq analysis to define specific transcriptional programs and regulated enhancer networks that are altered in distinct ovarian cell types or subtypes during aging. By defining the roles of specific enhancers in specific cell types, and how these change with aging, we aim to understand the identities of the regulatory factors and environmental signals that impact aging in each ovarian cell type. Genetic variation affecting enhancer selection and function is a major determinant of differences in cell-specific gene expression between individuals. To investigate the mechanisms by which altered regulatory enhancer landscapes contribute to ovarian aging by licensing changes in transcriptional programs, we will investigate the roles of genetic variants associated with age at menopause, detected by genome-wide association studies (GWAS), in modulating transcription programs during ovarian aging. In particular, we hope to provide mechanistic insights into genetic modulation of transcriptional regulation of critical homeostatic and inflammatory pathological functions in the granulosa cells (GC), the supporting cell type immediately surrounding the oocyte, by modeling the causal regulatory variants in human GC models that are differentiated from human ESCs engineered to carry causal variants by CRISPR gene editing.

生殖衰老是一个重大的健康、个人和社会问题，但卵巢衰老得到的关注有限