Wednesday, November 26, 2025 11/26/2025

Pyrimidine metabolism in the development of autoreactive B cells and SLE

Award Number: R01AI194568
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: 09/01/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Pyrimidine metabolism in the development of autoreactive B cells and SLE - PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a female-biased debilitating autoimmune disease that affects millions in America and worldwide. Antibody-forming cells (AFCs) and germinal centers (GCs) promote the development of autoreactive plasma cells (PCs) and the release of pathogenic autoantibodies (autoAbs) that are critical for the initiation and progression of disease manifestations including lupus nephritis. Mechanisms that promote the development of autoreactive B cells which drive SLE pathogenesis are incompletely understood. However, such knowledge is instrumental for developing much needed therapeutics that are preferable to current SLE treatment options that globally suppress the immune system and increase disease-associated morbidity and mortality. Metabolic reprogramming has emerged as a critical mechanism that underpins SLE autoimmune responses and disease progression. Various metabolic pathways are implicated in autoimmune responses in SLE. Although the importance of nucleotide metabolism has been described in cancer and purines such as ATP are essential for cellular metabolism, the role of pyrimidines in B cell metabolic reprogramming and responses in SLE is unknown. Importantly, drugs targeting the pyrimidine pathway are FDA approved for the treatment of cancer and rheumatoid arthritis. Drugs targeting the pyrimidine pathway is also considered for maintenance therapy for lupus nephritis with no major toxicity. However, the role of pyrimidine metabolism in autoreactive B cell development and pathogenic autoantibody (autoAb) production in AFC and GC pathways in SLE is not known. This grant will focus on delineating the mechanisms by which pyrimidine synthesis promotes systemic autoimmunity. The knowledge gained will be beneficial for dissecting mechanisms critical for B cell development and function and may lead to novel therapies for SLE and other B cell-mediated diseases. Our preliminary data highlighted the significance of de novo pyrimidine synthesis in autoreactive B cell responses in a SLE mouse model. Our data also indicated an interplay of pyrimidine metabolism and B cell metabolic reprogramming in SLE-prone B cells. Additional data pointed to a role for mTORc1, a master regulator of metabolism, in activating the pyrimidine pathway in SLE-prone B cells. We hypothesize that B cell-intrinsic pyrimidine metabolism and an interplay of de novo pyrimidine synthesis and metabolic networks promote autoreactive B cell development in AFC and GC pathways, leading to autoAb production and SLE. This hypothesis will be tested by three specific aims. Aim-1 will, for the first time, identify the cell-intrinsic mechanisms of pyrimidine metabolism in autoreactive B cell responses that promote the formation of autoAb-producing plasma cells and autoAbs in SLE. Aim-2 will determine the interplay of pyrimidine synthesis and B cell metabolic networks that promote autoreactive B cell development in SLE. Aim-3 will focus on the mechanism by which mTORc1 signaling drives the activation of de novo pyrimidine synthesis pathway in SLE-prone B cells.


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 = $2,989,958 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	8/26/2025	NEW	$2,989,958
														Subtotal = $2,989,958

Grand Total All Awards = $2,989,958

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Pyrimidine metabolism in the development of autoreactive B cells and SLE

Award Number: R01AI194568

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: 09/01/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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