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Tissue systems biology of immune dysregulation in aging by single cell spatial metabolomics

Award Number: R21AG081715
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Tissue systems biology of immune dysregulation in aging by single cell spatial metabolomics - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Aging Research	000	2	1/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $175,349 )
2024	2024	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Aging Research	000	2	2/9/2024	NON-COMPETING CONTINUATION	$157,815
2024	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Aging Research	001	2	7/3/2024	NON-COMPETING CONTINUATION	$17,534
														Subtotal = $175,349

Issue Date FY: 2023 ( Subtotal = $215,552 )
2023	2023	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Aging Research	000	1	5/10/2023	NEW	$215,552
														Subtotal = $215,552

Grand Total All Awards = $390,901

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Tissue systems biology of immune dysregulation in aging by single cell spatial metabolomics

Award Number: R21AG081715

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/15/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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