Regulatory Landscape of the Aging Human Ovary

人类卵巢衰老的调控景观

• 批准号: 10646190
• 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/10646190
• 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.

生殖衰老是一个主要的健康，个人和社会问题，但卵巢衰老已受到限制 即使在大型基因组调查项目中，科学的关注也是如此。卵巢衰老会影响各种健康状况 妇女包括寿命，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，卵巢衰老的基于的分子机制，更年期的时机和 器间反馈回路仍然难以捉摸。作为人体中最具动态的器官之一，卵巢 在整个生殖时期进行重大重塑。动态转录调节 衰老过程中卵母细胞及其周围细胞之间的相互作用和相互作用尚不清楚。目的 该提议是了解不同不同的相互作用的监管景观 卵巢中的细胞类型，并研究调节显着复杂的分子机制 生殖衰老的过程。我们将应用强大的单细胞（SC）RNA-seq和Scatac-Seq分析 定义特定的转录程序和调节的增强器网络，这些网络在不同的卵巢细胞中发生了变化 衰老期间的类型或亚型。通过定义特定增强子在特定细胞类型中的作用，以及如何 随着衰老的变化，我们旨在了解监管因素和环境信号的身份 每种卵巢细胞类型的影响衰老。影响增强子选择和功能的遗传变异是主要的 个体之间细胞特异性基因表达差异的决定因素。调查机制 通过许可变更的变更，改变的监管增强剂景观会导致卵巢老化 转录程序，我们将研究与年龄相关的遗传变异的作用， 通过全基因组关联研究（GWAS）检测到卵巢期间的转录程序 老化。特别是，我们希望对转录调控的遗传调节提供机械洞察力 颗粒细胞（GC）的关键体内平衡和炎症病理功能（支撑细胞） 通过对人GC模型中的因果调节变异进行建模，立即围绕卵母细胞的类型 通过CRISPR基因编辑携带因果变异的人类ESC的区别。