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
- 来源:
- 关键词:AgingAreaAtlasesBiologicalBiological MarkersBiological ModelsBone MarrowCell AgingCell Cycle ArrestCell ProliferationCellsCommunitiesDevelopmentDiseaseEnvironmentEpigenetic ProcessHematopoiesisHeterogeneityHumanImmuneInformaticsKidneyLiverLongevityLungLymphoid TissueMapsMolecularMolecular TargetNatural regenerationOrganPhenotypePhysiologyPlayProteinsPublished CommentPublishingResolutionResourcesRoleSCAP2 geneSpecimenStressTechnologyThymus GlandTissuesTonsilUnited States National Institutes of HealthValidationage relatedanalysis pipelinecell typedata resourcefunctional disabilityhealthspanhuman tissueimage visualizationimmune functionimprovedinsightlymph nodeslymphoid organmolecular imagingmultidisciplinaryrepairedsecondary lymphoid organsenescencesingle moleculesynergismtissue mappingtooltranscriptometranscriptomicswound healing
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)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Highly scalable and sensitive spatial transcriptomic and epigenomic sequencing of brain tissues from human and non-human primate
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- 批准号:
10370074 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
Yale TMC for Cellular Senescence in Lymphoid Organs
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10384399 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
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