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miR-21 regulation of autoreactive B cell and lupus nephritis development

Award Number: R01AI155666
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: 07/18/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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miR-21 regulation of autoreactive B cell and lupus nephritis development - Project Summary MicroRNAs (miRNAs) are critical post-transcriptional regulators of gene expression in immunity and autoimmunity, although many miRNAs remain poorly characterized. One such miRNA, miRNA-21 (miR-21), is upregulated in systemic lupus erythematosus (SLE) patients and promotes various diseases in mouse models. These include experimental autoimmune encephalomyelitis (EAE), asthma, cancer, and our findings on its role in toll-like receptor 7 (TLR7)-driven SLE in mice. We found that TLR7 overexpressing SLE-prone B6.Sle1bYaa mice deficient in miR-21 (Sle1bYaamiR-21-/-) had reduced germinal center (GC) B cell, T follicular helper (Tfh) cell and plasma cell (PC) responses. These responses in Sle1bYaamiR-21-/- mice were strongly associated with reduced autoantibody, and splenic and bone marrow autoantibody-producing antibody forming cell (AFC) responses. These data substantiate a role for miR-21 in the loss of B cell tolerance and autoimmunity, which necessitates identification of mechanisms (focus of the grant) by which miR-21 promotes autoantibody production and SLE. This will fill gaps in knowledge and may help discover an urgently needed targeted therapy for SLE, a debilitating disease that affects millions of Americans and people world-wide. TLR signaling, especially TLR7, promotes SLE in humans and murine models, and an attractive therapeutic target. TLR7 signaling activates the NF-kB inflammatory signaling pathway. TLR7 upregulates miR-21 expression in B cells which can target the negative regulator of NF-kB signaling, Peli1, although the role of miR-21 in regulating NF- kB signaling in SLE-prone B cells by targeting Peli1 is unknown. Preliminary data showed that B cells from Sle1bYaamiR-21-/- mice have increased Peli1 expression compared to control Sle1bYaa B cells. In addition, previous studies implicated TLR signaling in metabolic reprogramming, primarily through the activation of the PI3K/Akt/mTOR pathway in various immune conditions, although the role of this pathway in TLR7-mediated metabolic reprograming in B cells in SLE is not clear. miR-21 was also shown to regulate the PI3K/Akt/mTOR pathway in various models; however, its role in regulating B cell metabolism in TLR7-driven SLE is not known. Interestingly, our RNA-seq analysis of B cells from a TLR7-induced model showed negatively enriched genes in the PI3K/Akt/mTOR pathway in the absence of miR-21. Additional preliminary data showed increased extracellular acidification (ECAR) and oxygen consumption (OCR) rates in Sle1bYaa B cells overexpressing TLR7 compared to Sle1b B cells, indicating a more energetic phenotype in response to TLR7 signaling. Conversely, Sle1bYaamiR-21-/- B cells exhibited reduced ECAR and OCR compared to Sle1bYaa B cells. We hypothesize that miR-21 promotes TLR7-driven systemic autoimmune responses and SLE disease by regulating TLR7-NF-kB signaling and metabolic reprogramming in B cells. Proposed hypothesis and specific aims will help delineate the mechanism by which miR-21 drives autoimmune responses and lupus nephritis and will inform us whether miR-21 or miR-21 regulated pathway(s) can be a therapeutic target for SLE.


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 = $533,851 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	002	4	7/7/2025	NON-COMPETING CONTINUATION	$533,851
2025	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	2	1/21/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$39,931
2025	2022	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	1	1/21/2025	NEW	-$39,931
														Subtotal = $533,851

Issue Date FY: 2024 ( Subtotal = $537,976 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	7/16/2024	NON-COMPETING CONTINUATION	$537,976
														Subtotal = $537,976

Issue Date FY: 2023 ( Subtotal = $543,727 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	2	8/1/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$543,727
2023	2022	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	1	8/1/2023	NEW	$0
														Subtotal = $543,727

Issue Date FY: 2022 ( Subtotal = $563,050 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	1	7/18/2022	NEW	$563,050
														Subtotal = $563,050

Grand Total All Awards = $2,178,604

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miR-21 regulation of autoreactive B cell and lupus nephritis development

Award Number: R01AI155666

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: 07/18/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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