Regulatory Landscape of the Aging Human Ovary

人类卵巢衰老的调控景观

基本信息

项目摘要

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

项目成果

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MICHAEL G ROSENFELD其他文献

MICHAEL G ROSENFELD的其他文献

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{{ truncateString('MICHAEL G ROSENFELD', 18)}}的其他基金

Viral IncRNAs Regulate Host Genomic Transcriptional Programs Associated with Sporadic Alzheimer's Disease
病毒 IncRNA 调节与散发性阿尔茨海默病相关的宿主基因组转录程序
  • 批准号:
    10446865
  • 财政年份:
    2022
  • 资助金额:
    $ 33.25万
  • 项目类别:
Viral IncRNAs Regulate Host Genomic Transcriptional Programs Associated with Sporadic Alzheimer's Disease
病毒 IncRNA 调节与散发性阿尔茨海默病相关的宿主基因组转录程序
  • 批准号:
    10650398
  • 财政年份:
    2022
  • 资助金额:
    $ 33.25万
  • 项目类别:
Revealing the roles of HSV1 lytic and latent transcripts in AD pathogenesis and therapy
揭示 HSV1 裂解转录物和潜伏转录物在 AD 发病机制和治疗中的作用
  • 批准号:
    10621810
  • 财政年份:
    2021
  • 资助金额:
    $ 33.25万
  • 项目类别:
Regulatory Landscape of the Aging Human Ovary
人类卵巢衰老的调控景观
  • 批准号:
    10646190
  • 财政年份:
    2020
  • 资助金额:
    $ 33.25万
  • 项目类别:
Regulatory Landscape of the Aging Human Ovary
人类卵巢衰老的调控景观
  • 批准号:
    10264170
  • 财政年份:
    2020
  • 资助金额:
    $ 33.25万
  • 项目类别:
Regulatory Landscape of the Aging Human Ovary
人类卵巢衰老的调控景观
  • 批准号:
    10091772
  • 财政年份:
    2020
  • 资助金额:
    $ 33.25万
  • 项目类别:
A stress-induced promoter pause release program in cardiomyocytes protecting against myocardial infarction
心肌细胞中应激诱导的启动子暂停释放程序可预防心肌梗死
  • 批准号:
    10521252
  • 财政年份:
    2019
  • 资助金额:
    $ 33.25万
  • 项目类别:
Combinatorial regulation of the enhancer codes in senescence
衰老过程中增强子密码的组合调控
  • 批准号:
    10152492
  • 财政年份:
    2019
  • 资助金额:
    $ 33.25万
  • 项目类别:
A stress-induced promoter pause release program in cardiomyocytes protecting against myocardial infarction
心肌细胞中应激诱导的启动子暂停释放程序可预防心肌梗死
  • 批准号:
    10318093
  • 财政年份:
    2019
  • 资助金额:
    $ 33.25万
  • 项目类别:
Combinatorial regulation of the enhancer codes in senescence
衰老过程中增强子密码的组合调控
  • 批准号:
    10017129
  • 财政年份:
    2019
  • 资助金额:
    $ 33.25万
  • 项目类别:

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