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Characterizing the negative signaling in dendritic cells and macrophages to attenuate inflammation and bone destruction in rheumatoid arthritis

Award Number: R01AR074954
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Characterizing the negative signaling in dendritic cells and macrophages to attenuate inflammation and bone destruction in rheumatoid arthritis - The goal of this proposal is to understand the mechanisms underlying how negative endogenous signaling reduces chronic inflammation in rheumatoid arthritis (RA), which can provide novel therapeutic targets for diseases related to inflammation and tissue destruction. Current therapies for RA have serious negative effects on the patients’ immune system, and can cause malignancies, pneumonia, and tuberculosis. Positive regulators of inflammation in RA (such as NF-κB) have been well characterized, however, the negative endogenous regulators of RA-induced inflammation and bone destruction, especially in macrophages and dendritic cells in RA pathological condition remain elusive. The proposed study will characterize the negative endogenous regulators of differentiation and activity in macrophages and dendritic cells (DCs) that attenuate RA-induced inflammation and tissue destruction. We noted that Gα13 deficiency in macrophages or dendritic cells aggravated inflammation in mouse RA model. AAV mediated overexpression of local Gna13 constitutively active form (Gna13CA) not only significantly reduced bone destruction, but also dramatically inhibited inflammation in RA, indicating that Gna13CA could protect against inflammation in a mouse model of RA. Our RNA sequencing (RNA-seq) analysis showed that Gα13 may negatively regulate macrophage and DC differentiation and activation and ChIP sequencing (ChIP-seq) analysis showed the enrichment of NF-κB motif site binding on the genome-wide promoters of the genes related to inflammation in Gα13 deficient macrophages with TNFα or LPS stimulations. Our preliminary data showed that Gα13 deficiency promotes Akt activity, STAT3 phosphorylation and NF-κB signaling pathway activation in dendritic cells and macrophages. Based on our preliminary studies, we hypothesize that Gα13 is a master negative regulator that attenuates inflammation and bone destruction associated with rheumatoid arthritis through the Gα13/RhoA/AKT/IKK/NF-κB pathway in macrophages and dendritic cells. Three specific aims are proposed to test our hypothesis. In Aim 1, we will determine the role of Gα13 in inflammation and bone destruction in rheumatoid arthritis (RA) by characterizing the phenotypes and pathomechanism of conditional knockout (CKO) mouse models via loss-of-function approach in RA. In Aim 2, we will define the roles and therapeutic effects of Gα13CA in inflammation and bone destruction in RA by characterizing the phenotypes and pathomechanism of conditional transgenic overexpression (OE) mouse models via gain-of-function approach in RA. We will characterize the molecular mechanism by which Gα13 regulates inflammation and bone destruction in RA through Gα13/ RhoA/AKT/IKK/NF-κB signaling, STAT3 signaling, and TLRs signaling pathways in macrophages and dendritic cells in Aim 3. The proposed study will provide important insights into the negative regulation of the cells of the immune system to effectively target inflammation and bone destruction in RA. Knowledge gained from this study may bring forth potential superior therapeutic means for treating RA and other inflammatory bone diseases.


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: 2024 ( Subtotal = $324,368 )
2024	2024	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	6/10/2024	NON-COMPETING CONTINUATION	$23,407
2024	2024	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	12/18/2023	NON-COMPETING CONTINUATION	$300,961
														Subtotal = $324,368

Issue Date FY: 2023 ( Subtotal = $334,400 )
2023	2023	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/7/2023	NON-COMPETING CONTINUATION	$300,960
2023	2023	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	4/20/2023	NON-COMPETING CONTINUATION	$33,440
														Subtotal = $334,400

Issue Date FY: 2022 ( Subtotal = $331,053 )
2022	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	005	4	5/1/2022	NON-COMPETING CONTINUATION	$331,053
2022	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	004	3	2/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	10/23/2021	NON-COMPETING CONTINUATION	-$22,869
2022	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	10/23/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$178,050
2022	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	3	10/25/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	10/23/2021	NEW	-$155,181
														Subtotal = $331,053

Issue Date FY: 2021 ( Subtotal = $323,829 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/22/2020	NON-COMPETING CONTINUATION	$294,030
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	6/8/2021	NON-COMPETING CONTINUATION	$22,869
2021	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	3	9/2/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$300,960
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	2	9/1/2021	NON-COMPETING CONTINUATION	-$294,030
														Subtotal = $323,829

Issue Date FY: 2020 ( Subtotal = $326,700 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/14/2020	NEW	$326,700
														Subtotal = $326,700

Grand Total All Awards = $1,640,350

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Characterizing the negative signaling in dendritic cells and macrophages to attenuate inflammation and bone destruction in rheumatoid arthritis

Award Number: R01AR074954

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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