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Hydrogel-Based Aged Immune Organoids to Study Epigenetics and Trajectory of B Cells

Award Number: R01AI181282
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/12/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Hydrogel-Based Aged Immune Organoids to Study Epigenetics and Trajectory of B Cells - PROJECT SUMMARY Aged individuals, who are often at higher risk of fatality in life-threatening infectious diseases, do not form high- quality antibodies against new infections. Humoral immunity against infections depends on the germinal center (GC) differentiation process in the B cell follicles of lymph nodes. In GCs, naïve B cells rapidly proliferate in response to T cell-dependent antigens and somatically mutate into high-affinity antibody-secreting cells, i.e., plasma cells. A significant concern is that with aging, B cells exhibit a decreased expansion of B cells and GC reaction in response to antigen. However, it is unclear whether this is solely due to immune senescence and a defect in B cells or the follicular T helper cell (TFH), and whether the lymphoid microenvironment of B cell follicles plays a role. B cells in young mice assume heterogeneous cell fates upon stimulation, with only a fraction differentiating into antibody-secreting cells (ASC), however, this phenomenon remains unknown in B cells from old mice. Notably, plasma cell differentiation in young B cells is controlled by multiple cell division-coupled epigenetic programs, which also remains understudied in old B cells. Because aged mice cannot generate sufficient GCs to provide insight into ASC fate and epigenomic remodeling of GC B cells, necessitating the development of a tissue-engineered model of aged lymphoid tissues. The long-term goals of this R01 are 1) to develop an ex vivo “aged B cell follicle” organoid technology capable of providing lymphoid microenvironment signals in a plug-and-play manner to induce early GC programming of aged B cells from mice and human B cells, therefore enabling the study of plasma cell fate and regulation of the epigenome of B cells; and 2) to identify checkpoint targets that can be suppressed to boost GC response in aged B cells. PI has demonstrated that GCs phenotype could be generated in organoids using B cells from >2-yr old mice when differentiated under young lymphoid microenvironment conditions, however to a lesser extent than young B cells. However, true differentiation fate of aged B cells ex vivo can only be realized in a microenvironment representative of old lymph nodes.The R01 is highly significant and innovative because it will 1) establish lymphoid microenvironment of aged lymph nodes and engineer a hydrogel-based “aged” immune organoid to study vaccine and infection responses, 2) enable control over the ex vivo B cell differentiation of aged B cells in ex vivo cultures and generate antigen-specific antibodies against infections, 3) define the cell division kinetics of B cell differentiation and identify the molecular and epigenetic trajectories of aged B cell fate and ASC formation, and 4) identify checkpoint targets to accelerate GCs 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: 2026 ( Subtotal = $734,360 )
2026	2026	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Allergy and Infectious Diseases Research	000	3	6/9/2026	NON-COMPETING CONTINUATION	$734,360
														Subtotal = $734,360

Issue Date FY: 2025 ( Subtotal = $741,009 )
2025	2025	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Allergy and Infectious Diseases Research	000	2	5/22/2025	NON-COMPETING CONTINUATION	$741,009
														Subtotal = $741,009

Issue Date FY: 2024 ( Subtotal = $771,620 )
2024	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Allergy and Infectious Diseases Research	000	1	7/12/2024	NEW	$695,893
2024	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Allergy and Infectious Diseases Research	002	1	9/4/2024	NEW	$75,727
2024	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Allergy and Infectious Diseases Research	001	1	7/17/2024	NEW	$0
														Subtotal = $771,620

Grand Total All Awards = $2,246,989

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Hydrogel-Based Aged Immune Organoids to Study Epigenetics and Trajectory of B Cells

Award Number: R01AI181282

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/12/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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