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，但卵巢衰老受到的影响有限 科学界的关注，即使是在大型基因组调查项目中。卵巢衰老影响多种健康结果 女性，包括寿命、心血管疾病、代谢综合征、神经退行性疾病和 各种类型的癌症。然而，卵巢衰老、绝经时间和卵巢衰老的分子机制 器官间反馈回路仍然难以捉摸。卵巢作为人体最具活力的器官之一 在整个生殖期经历显着的重塑。动态转录调控 衰老过程中卵母细胞与其周围细胞的相互作用以及它们之间的相互作用仍然未知。的目标 该提案旨在了解不同监管机构之间复杂相互作用背后的监管环境 卵巢中的细胞类型并研究调节非常复杂的分子机制 生殖衰老过程。我们将应用强大的单细胞 (sc) RNA-seq 和 scATAC-seq 分析来 定义在不同卵巢细胞中改变的特定转录程序和调节增强子网络 衰老过程中的类型或亚型。通过定义特定增强子在特定细胞类型中的作用，以及这些增强子如何 随着年龄的增长而变化，我们的目标是了解调节因素和环境信号的身份 影响每种卵巢细胞类型的衰老。影响增强子选择和功能的遗传变异是一个主要因素 个体之间细胞特异性基因表达差异的决定因素。研究机制 调节增强子景观的改变通过许可变化导致卵巢衰老 转录程序，我们将研究与绝经年龄相关的遗传变异的作用， 通过全基因组关联研究（GWAS）发现，在卵巢期间调节转录程序 老化。特别是，我们希望为转录调控的遗传调节提供机制见解 颗粒细胞（GC）（支持细胞）中关键的稳态和炎症病理功能 通过对人类 GC 模型中的因果调控变异进行建模，可以确定紧邻卵母细胞周围的类型 与通过 CRISPR 基因编辑设计携带因果变异的人类 ESC 不同。