Decoding Spatially Resolved Single Cell Metabolic Trajectory of Tonsil Tissues and Organoids
解码扁桃体组织和类器官的空间分辨单细胞代谢轨迹
基本信息
- 批准号:10751125
- 负责人:
- 金额:$ 19.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-10 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAntibody AffinityAntigensB-Cell DevelopmentB-Lymphocyte SubsetsB-LymphocytesBiocompatible MaterialsBioinformaticsCellsCellular Metabolic ProcessChildhoodClonal ExpansionCoculture TechniquesCytokine GeneDataDefectEngineeringExhibitsExposure toFatty AcidsGene Expression ProfilingGoalsHumanHumoral ImmunitiesImmune responseImmune systemImpairmentIndividualInfectionInfluenzaLifeLipidsMapsMetabolicMetabolic syndromeMetabolismModelingObstructive Sleep ApneaOrganoidsPatientsPhysiologicalProliferatingProteomicsReactionResearchRoleSiteSpatial DistributionStructureStructure of germinal center of lymph nodeT-LymphocyteTechnologyTestingTissuesTonsilfluhuman tissueinfluenza infectioninnovationinsightmetabolomicsresponsesecondary lymphoid organ
项目摘要
Germinal centers (GCs) are the microstructural sites in secondary lymphoid organs that control B cell clonal
expansion to produce high-affinity antibodies for achieving humoral immunity. GC structures are impaired in
obstructive sleep apnea (OSA) patients, leading the deficiencies in immune responses in infected individuals.
The role of B cell development through GC reactions has been well established. B-cell immunometabolism is
crucial to meet the energy needs of rapid proliferation. OSA patients exhibited associations with metabolic
syndrome and vulnerability to flu. However, the coordination of metabolic trajectories in B cells of OSA+ and
OSA- patients is still not clearly understood. There is a critical need to decipher the B cell immunometabolism
at the single cell level in GCs for identifying the metabolic defects in the immune system of OSA patients
making them prone to life-threatening infections. Thus, this project will leverage the recently developed
spatially resolved metabolic profiling framework (3D-SMF) to map B cell subsets and their metabolism in the
tonsil tissues and organoids. Our long-term goal is to generate single cell metabolic insights of B cell
development in GCs of OSA+ and OSA- patients in response to influenza. The goal of this project is to define
spatially resolved B cell immunometabolism pixel-by-pixel in fixed human tissues and living tissues. We
hypothesize that metabolic trajectories and spatial distributions of B-cell subsets will be defective in OSA+
compared to OSA- tissues and influenza response in OSA- tonsil-derived organoids will be more competent
than OSA+ tonsil-derived organoids. The rationale for this hypothesis is based on the 3D-SMF data showing
the depletion and enrichment of fatty acids in GCs located in native tonsil tissues and the recent evidence on
OSA patients’ vulnerability to flu infections associated with metabolic syndrome. The central hypothesis will be
tested by pursuing two specific Aims. Aim 1 will provide an integral understanding of the lipid-associated
immunometabolism in B-cell subsets in human OSA+ and OSA- tonsil tissues (n=10 each) and engineered
tonsil organoids. Aim 2 will define how the metabolic trajectory modeling of B cell subtypes differs in tonsil
organoids exposed to influenza antigens in OSA+ and OSA- donors. To accomplish these Aims, 3D-SMF and
multiplexed cytokine gene expression profiling will be used to analyze B cell immunometabolism through a
pseudotime B cell development modeling and longitudinal metabolic trajectory comparisons of B cell subsets in
biomaterial-based tonsil organoids. This project builds an interdisciplinary team integrating experts from
spatial omics, biomaterials, pediatric OSA, and bioinformatics. The proposed application is innovative
because it uses cutting-edge technology to define spatial metabolomics and proteomics of tonsil organoids and
shifts from the traditional focus on T cell and B cell co-cultures, toward differences of B cell metabolism in
physiologically relevant and dynamic OSA+ and OSA- tonsil organoids ex vivo. This research is significant
because it defines B cell immunometabolism to understand why OSA patients are prone to flu infections.
生发中心(GCs)是次级淋巴器官中控制B细胞克隆的微结构部位
扩增产生高亲和力抗体以实现体液免疫。GC结构受损
阻塞性睡眠呼吸暂停(OSA)患者,导致感染者免疫反应缺陷。
通过GC反应发展B细胞的作用已经得到了很好的证实。B细胞的免疫代谢是
对满足快速扩散的能源需求至关重要。阻塞性睡眠呼吸暂停患者与代谢相关
综合症和对流感的脆弱性。然而,OSA+和OSA+在B细胞中代谢轨迹的协调
阻塞性睡眠呼吸暂停综合征患者仍不清楚。迫切需要破译B细胞的免疫代谢
单细胞水平检测阻塞性睡眠呼吸暂停综合征患者免疫系统代谢缺陷
使他们容易受到危及生命的感染。因此,该项目将利用最近开发的
空间分辨代谢谱框架(3D-SMF)定位B细胞亚群及其代谢
扁桃体组织和器官。我们的长期目标是产生对B细胞的单细胞代谢洞察力
OSA+和OSA-患者对流感反应的GC的发展。这个项目的目标是定义
在固定的人体组织和活组织中逐个像素地空间分辨B细胞免疫代谢。我们
假设OSA+患者B细胞亚群的代谢轨迹和空间分布存在缺陷
与OSA组织和流感反应相比,OSA-扁桃体衍生的有机物将更有能力
而不是OSA+扁桃体衍生的有机化合物。这一假设的理论基础是基于3D-SMF数据显示
天然扁桃体组织中GC中脂肪酸的耗竭和富集性及其最新证据
阻塞性睡眠呼吸暂停综合征患者对与代谢综合征相关的流感感染的脆弱性。中心假设将是
通过追求两个具体目标来检验。目标1将提供对与脂质相关的
人OSA+和OSA-扁桃体组织中B细胞亚群的免疫代谢
扁桃体器官。目标2将定义扁桃体中B细胞亚型的代谢轨迹模型如何不同
OSA+和OSA-献血者暴露于流感抗原的有机物。为了实现这些目标,3D-SMF和
多路细胞因子基因表达谱将用于分析B细胞的免疫代谢
中国人B细胞亚群的伪时间发育模型及纵向代谢轨迹比较
以生物材料为基础的扁桃体有机化合物。该项目建立了一个跨学科的团队,整合了来自
空间组学、生物材料、儿科OSA和生物信息学。拟议的应用程序是创新的
因为它使用尖端技术来定义扁桃体器官的空间代谢组学和蛋白质组学
从传统的T细胞和B细胞共培养转向B细胞代谢的差异
体外生理相关和动态的OSA+和OSA-扁桃体有机化合物。这项研究具有重要的意义
因为它定义了B细胞免疫新陈代谢,以理解为什么OSA患者容易感染流感。
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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Ahmet F. Coskun其他文献
Clinically relevant clot resolution via a thromboinflammation-on-a-chip
通过芯片上血栓炎症实现临床相关的血栓溶解
- DOI:
10.1038/s41586-025-08804-7 - 发表时间:
2025-04-02 - 期刊:
- 影响因子:48.500
- 作者:
Yongzhi Qiu;Jessica Lin;Audrey Wang;Zhou Fang;Yumiko Sakurai;Hyoann Choi;Evelyn K. Williams;Elaissa T. Hardy;Kristin Maher;Ahmet F. Coskun;Gary Woods;Wilbur A. Lam - 通讯作者:
Wilbur A. Lam
A Dynamic Personalized Human 3D Organoid for the Study of the Tumor Microenvironment and Metabolism in Acute Myeloid Leukemia Using Patient-Derived Xenografts
- DOI:
10.1182/blood-2022-170225 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:
- 作者:
Alejandro De Janon;Madison Stout;Diana Fridlyand;Zhou Fang;Ahmet F. Coskun;Douglas K Graham;Athanasios Mantalaris;Deborah DeRyckere;Nicki Panoskaltsis - 通讯作者:
Nicki Panoskaltsis
Decoding senescence of aging single cells at the nexus of biomaterials, microfluidics, and spatial omics
在生物材料、微流控和空间组学的交汇处解码衰老的衰老单细胞
- DOI:
10.1038/s41514-024-00178-w - 发表时间:
2024-11-26 - 期刊:
- 影响因子:6.000
- 作者:
Abhijeet Venkataraman;Ivan Kordic;JiaXun Li;Nicholas Zhang;Nivik Sanjay Bharadwaj;Zhou Fang;Sandip Das;Ahmet F. Coskun - 通讯作者:
Ahmet F. Coskun
Ahmet F. Coskun的其他文献
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{{ truncateString('Ahmet F. Coskun', 18)}}的其他基金
Dissecting subcellular and cellular organization by spatial molecular neighborhood networks
通过空间分子邻域网络剖析亚细胞和细胞组织
- 批准号:
10713565 - 财政年份:2023
- 资助金额:
$ 19.68万 - 项目类别:
Tissue systems biology of immune dysregulation in aging by single cell spatial metabolomics
通过单细胞空间代谢组学研究衰老过程中免疫失调的组织系统生物学
- 批准号:
10647249 - 财政年份:2023
- 资助金额:
$ 19.68万 - 项目类别:
Tracing spatial organization of germinal centers in rhesus macaques
追踪恒河猴生发中心的空间组织
- 批准号:
10762072 - 财政年份:2023
- 资助金额:
$ 19.68万 - 项目类别:
Spatial transcriptional phenotyping of Sjögren’s disease tissue-resident mesenchymal stromal cells and neighbors in labial salivary glands
干燥病组织驻留间充质基质细胞和唇唾液腺邻近细胞的空间转录表型
- 批准号:
10575107 - 财政年份:2023
- 资助金额:
$ 19.68万 - 项目类别:
Spatial Epigenomic Profiling of Immune Cell Signatures at Subcellular Resolution in Health and Disease
健康和疾病中免疫细胞特征的亚细胞分辨率空间表观基因组分析
- 批准号:
10065913 - 财政年份:2018
- 资助金额:
$ 19.68万 - 项目类别:
Spatial Epigenomic Profiling of Immune Cell Signatures at Subcellular Resolution in Health and Disease
健康和疾病中免疫细胞特征的亚细胞分辨率空间表观基因组分析
- 批准号:
10425357 - 财政年份:2018
- 资助金额:
$ 19.68万 - 项目类别:
Spatial Epigenomic Profiling of Immune Cell Signatures at Subcellular Resolution in Health and Disease
健康和疾病中免疫细胞特征的亚细胞分辨率空间表观基因组分析
- 批准号:
10201436 - 财政年份:2018
- 资助金额:
$ 19.68万 - 项目类别:
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