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.
生发中心是次级淋巴器官中控制B细胞克隆形成的微结构部位
扩增以产生用于实现体液免疫的高亲和力抗体。GC结构受损,
阻塞性睡眠呼吸暂停(OSA)患者,导致感染个体免疫反应的缺陷。
B细胞通过GC反应发育的作用已得到充分证实。B细胞免疫代谢是
这对满足快速扩散的能源需求至关重要。OSA患者表现出与代谢相关的
综合症和易患流感。然而,OSA+和OSA+的B细胞中代谢轨迹的协调是不一致的。
OSA-患者仍然不清楚。迫切需要破译B细胞免疫代谢
在GC中的单细胞水平用于鉴定OSA患者免疫系统中的代谢缺陷
使他们容易受到威胁生命的感染。因此,该项目将利用最近开发的
空间分辨代谢分析框架(3D-SMF),以绘制B细胞亚群及其在
扁桃体组织和类器官。我们的长期目标是产生B细胞的单细胞代谢见解
OSA+和OSA-患者响应流感的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像素的空间分辨B细胞免疫代谢。我们
假设B细胞亚群的代谢轨迹和空间分布在OSA+中是有缺陷的,
与OSA-组织和OSA-扁桃体衍生类器官中的流感反应相比,
OSA+扁桃体衍生的类器官。该假设的依据是3D-SMF数据,显示
天然扁桃体组织中GC中脂肪酸的消耗和富集,以及最近的证据表明,
阻塞性睡眠呼吸暂停综合征患者易受流感感染与代谢综合征有关。核心假设是
通过追求两个具体目标进行测试。目的1将提供一个整体的了解脂质相关的
人OSA+和OSA-扁桃体组织中B细胞亚群的免疫代谢(各n=10)和工程化
扁桃体类器官目的2将定义扁桃体中B细胞亚型的代谢轨迹建模如何不同
OSA+和OSA-供体中暴露于流感抗原的类器官。为了实现这些目标,3D-SMF和
多重细胞因子基因表达谱将用于分析B细胞免疫代谢,
假时间B细胞发育建模和慢性乙型肝炎患者B细胞亚群的纵向代谢轨迹比较
生物材料基扁桃体类器官。该项目建立了一个跨学科的团队,
空间组学、生物材料、小儿OSA和生物信息学。建议的应用是创新的
因为它使用尖端技术来定义扁桃体类器官的空间代谢组学和蛋白质组学,
从传统的关注T细胞和B细胞共培养转向B细胞代谢的差异,
生理学相关的和动态的OSA+和OSA-离体扁桃体类器官。这项研究意义重大
因为它定义了B细胞的免疫代谢,以了解为什么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:
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:
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 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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