Defining Epigenetic States of Senescent Cells and Associated Tissue Environments in the Human Lymphoid Tissues

定义人类淋巴组织中衰老细胞和相关组织环境的表观遗传状态

基本信息

  • 批准号:
    10666979
  • 负责人:
  • 金额:
    $ 20万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-30 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Cell senescence in human tissues is an irreversible cell cycle arrest state in otherwise proliferative cells, which is a hallmark of aging that alters the tissue environments via senescence-associated secretory phenotype (SASP) but may also play a beneficial role in tissue remodeling, regeneration, and wound healing. Lymphoid organs play a vital role in hematopoiesis and immune function. How cellular senescence in these tissues is associated with stress-induced or age-related functional impairment, what types or subtypes of senescent cells are present and their spatial heterogeneity and how these cells impact the tissue environments remain poorly understood, precluding the development of strategies to target senescent cells to improve healthspan/lifespan or harnessing these cells or secreted factors to promote tissue remodeling and repair. A recent commentary published in Cell by NIH identified five broad areas (atlases, imaging &visualization, biomarkers, model systems, perturbation and validation) that would help propel the field forward. Our application will assemble a multidisciplinary team to tackle all these areas and specifically, as a Tissue Mapping Center (TMC), will focus on generating the molecular and cellular maps of cellular senescence and associated tissue environments in 4 primary and secondary lymphoid organs. Specifically, it will (a) collect, analyze, annotate, and share high quality non-diseased human primary (bone marrow and thymus) and secondary (tonsil and lymph node) lymphoid tissues, (2) develop and deploy a suite of high-resolution, high-content and high-throughput single- cell & spatial omics technologies to characterize these specimens and paired biofluids, and (3) perform integrated informatics to identify biomarkers of senescent cell heterogeneity and to construct comprehensive molecular and cellular maps of cellular senescence and associated environments in these organs. Four major biological analysis pipelines are: (1) single-cell high-plex (>40) protein secretome profiling, (2) single-cell proteo-transcriptomic sequencing (scCITE-seq), (3) spatial proteo-transcriptomic sequencing at cellular level (DBiT-seq for co-mapping whole transcriptome and a panel of ~300 proteins at cellular level with 10µm pixel size), and (4) spatial molecular imaging (SMI) of ~1,000 molecular targets in FFPE tissues at single-molecule subcellular resolution. With these unique tools, we will (a) characterize functional SASP heterogeneity and identify biomarkers of SAPS in different cell types, (b) construct molecular and cellular maps in 4 human lymphoid tissues, and (c) identify biomarkers of cellular senescence in tissue and the associated environments, contributing to the resource building of SenNet. Since the immune function is central to the physiology of all major organs, our study will provide insights to the role of senescent immune cells in development, aging, or disease in other organs like gut, lung, liver, and kidney, representing a strong synergy within SenNet and the wider scientific community.
项目总结

项目成果

期刊论文数量(0)
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Rong Fan其他文献

Rong Fan的其他文献

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{{ truncateString('Rong Fan', 18)}}的其他基金

Core B - Biological Analysis
核心 B - 生物分析
  • 批准号:
    10553034
  • 财政年份:
    2022
  • 资助金额:
    $ 20万
  • 项目类别:
Core B - Biological Analysis
核心 B - 生物分析
  • 批准号:
    10675115
  • 财政年份:
    2022
  • 资助金额:
    $ 20万
  • 项目类别:
Core 2: Tissue Imaging and Profiling Core
核心 2:组织成像和分析核心
  • 批准号:
    10708933
  • 财政年份:
    2022
  • 资助金额:
    $ 20万
  • 项目类别:
Core 2: Tissue Imaging and Profiling Core
核心 2:组织成像和分析核心
  • 批准号:
    10526107
  • 财政年份:
    2022
  • 资助金额:
    $ 20万
  • 项目类别:
Highly scalable and sensitive spatial transcriptomic and epigenomic sequencing of brain tissues from human and non-human primate
对人类和非人类灵长类动物的脑组织进行高度可扩展且灵敏的空间转录组和表观基因组测序
  • 批准号:
    10370074
  • 财政年份:
    2021
  • 资助金额:
    $ 20万
  • 项目类别:
Core A: Administrative Core
核心A:行政核心
  • 批准号:
    10384400
  • 财政年份:
    2021
  • 资助金额:
    $ 20万
  • 项目类别:
Core C: Biological Analysis Core
核心C:生物分析核心
  • 批准号:
    10384403
  • 财政年份:
    2021
  • 资助金额:
    $ 20万
  • 项目类别:
Yale TMC for Cellular Senescence in Lymphoid Organs
耶鲁大学 TMC 研究淋巴器官细胞衰老
  • 批准号:
    10384399
  • 财政年份:
    2021
  • 资助金额:
    $ 20万
  • 项目类别:
Core A: Administrative Core
核心A:行政核心
  • 批准号:
    10689276
  • 财政年份:
    2021
  • 资助金额:
    $ 20万
  • 项目类别:
Core C: Biological Analysis Core
核心C:生物分析核心
  • 批准号:
    10689284
  • 财政年份:
    2021
  • 资助金额:
    $ 20万
  • 项目类别:

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