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
• 负责人: Ahmet F. Coskun
• 金额: $ 21.56万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647249
• 关键词: 3-Dimensional; Affinity; Age; Aging; Anatomy; Antibodies; Antibody Formation; B Cell Proliferation; B-Cell Activation; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Biochemical Pathway; Bioinformatics; Biomedical Engineering; Biometry; Biotechnology; CD4 Positive T Lymphocytes; Cell Aging; Cell Cycle Arrest; Cell Maturation; Cell secretion; Cells; Cellular Metabolic Process; Cellular biology; Chemicals; Cholesterol; Collaborations; Data; Defect; Deterioration; Dissociation; Elderly; Enzymes; Event; Exhibits; Fatty Acids; Fingerprint; Genes; Goals; Helper-Inducer T-Lymphocyte; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunoglobulin Somatic Hypermutation; Immunology; Impairment; Individual; Infection; Inflammation; Knowledge; Lipids; Location; Lymph Node Tissue; Lymphoid Cell; Lymphoid Tissue; Maps; Measures; Memory B-Lymphocyte; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Mission; Modeling; Molecular; Mutate; Neighborhoods; Organ; Pathologic; Pathway interactions; Phenotype; Phosphatidylethanolamine; Physiological; Plasma Cells; Play; Population; Proliferating; Proteomics; Protocols documentation; Public Health; Reaction; Regulation; Research; Resolution; Role; Specialized Center; Stromal Cells; Structure; Structure of germinal center of lymph node; Systems Biology; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Technology; Testing; Tissues; Tonsil; Vaccines; age group; age related; aged; cell type; experience; fatty acid oxidation; glucose metabolism; human tissue; innovation; insight; lipid metabolism; lymph nodes; lymphoid organ; metabolic abnormality assessment; metabolomics; network models; pathogen; programs; protein profiling; response; secondary lymphoid organ; senescence; small molecule; tool

The immune system changes with age and gradually leads to incompetent immune responses against pathogens. Immune cells experience senescence, an irreversible cell cycle arrest, and secrete senescence- associated secretory phenotype (SASP) factors, causing pathological alterations of spatial organization and cell types in the germinal centers (GCs) of lymphoid organs. GC structures are impaired in the elderly population, reducing antibody production in aging individuals. B cell immunometabolism is crucial to meet the energy needs of rapid proliferation, somatic hypermutation, and affinity-based selection in GCs. However, the coordination of metabolic pathways in T follicular helper cells (TFH) and GC B cells is still not clearly understood. There is a critical need to decipher the TFH-dependent B cell immunometabolism at the single cell level in GCs for identifying aging-associated molecular defects. Thus, this project will leverage the recently developed spatially resolved metabolic profiling framework (3D-SMF) that maps the CD4+ T cell and B cell subsets and their metabolic correlates in native lymphoid tissues. Our long-term goal is to generate single cell metabolic insights of TFH-dependent B cell development in GCs of elderly individuals compared to young ones. The goal of this project is to define spatially resolved B cell immunometabolism pixel-by-pixel in fixed human tonsil and lymph node tissues. We hypothesize that unique metabolic programs of cellular senescence and SASP factor diversity are regulated by lipid metabolism events, causing age-dependent unique immunity; and these programs are distinctively potent in subtypes of secondary lymphoid organs in younger aged groups compared to the older ones. The rationale for this hypothesis is based on the 3D-SMF data showing depletion and enrichment of fatty acids in GCs located in native tonsil tissues. The central hypothesis will be tested by pursuing two specific Aims. Aim 1 will provide a deeper understanding of the lipid-associated immunometabolism in TFH cells and B-cell subsets (naïve, GC B cells, and plasma cells) in human tonsil tissues. Aim 2 will define how the metabolic network modeling of TFH and B cell subtypes and overall cell composition differs in lymph nodes in comparison to tonsil tissues. To accomplish these Aims, 3D-SMF and multiplexed enzyme profiling will be used to analyze B cell immunometabolism using a metabolic network comparison of B cell subsets in native tonsils and lymph nodes. This project builds an interdisciplinary team integrating experts from single cell biotechnology, bioengineering, inflammation in aging, metabolic modeling, and bioinformatics. The proposed application is innovative because it uses cutting-edge technology to define spatial metabolomics and proteomics of tonsil and lymph node tissues without dissociation protocols and shifts from the traditional focus on isolating T cell and B cells from their native microenvironment to study immune defects in aging. This research is significant because it defines TFH-dependent B cell immunometabolism in lymphoid tissues to decipher single-cell metabolic fingerprints of immune dysregulation in aging.

免疫系统随着年龄的增长而变化，并逐渐导致免疫应答能力下降