Friday, April 19, 2024 4/19/2024

Characterizing the mechanism by which endogenous negative regulators of osteoclasts control bone homeostasis under physiological and pathological conditions in mouse models

Award Number: R01AR070135
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

The immediate goal of this application is to understand how osteoclast (OC) differentiation is regulated through negative endogenous regulators, which may provide novel therapeutic targets for bone diseases, such as osteoporosis and rheumatoid arthritis (RA). Although positive regulators of OC differentiation through the receptor activator of nuclear factor kB (RANK) ligand (RANKL)-RANK signaling axis have been extensively studied, understanding of negative regulators of OC differentiation is elusive. To identify key negative regulators of OC differentiation, we utilized microarray, gene downregulation, and osteoclastogenesis assays, leading to the isolation of guanine protein alpha subunit 13 (Ga13, encoded by the Gna13 gene) as a potential OC negative regulator. To enable in vivo investigation of the role of Ga13 in OC differentiation, we generated an OC-lineage specific Gna13 conditional knockout (CKO) mouse model by crossing Gna13f/f mice with LysM-Cre (OC precursor specific) mice. Our preliminary data showed that Gna13f/fLysM-Cre mice exhibited a severe osteoporosis from a drastic increase in OC differentiation. We also noted that Ga13 deficiency attenuates RhoA activity and promotes Akt activity in OCs. Consistently, we showed that, as a proof of principle strategy, local constitutively active Ga13 overexpression can protect against bone and cartilage loss while also attenuating inflammation in a mouse model of RA. Based on our preliminary data, we hypothesize that Ga13 is a key negative regulator of OC that controls OC cell lineage commitment and differentiation for bone homeostasis under physiological and pathological conditions through activating RhoA and attenuating AKT signaling pathway. Three specific aims are proposed to test our hypothesis. In Aim 1, we will characterize the bone phenotypes of Gna13f/fLysM-Cre mice and elucidate the mechanism underlying how Ga13 activates RhoA signaling and attenuates Akt signaling to negatively regulate OC cell lineage commitment and differentiation. In Aim 2 we will determine the upstream Ga13 signaling cascade in OCs through characterization of G protein coupled receptors (GPCRs) coupled with Ga13. We will characterize the mechanism underlying the roles of Ga13 in bone remodeling and pathological bone loss by using dendritic cell (DC)-, monocyte- and OC-specific Gna13 CKO and overexpression transgenic mice in the loss-of-function and gain-of-function analysis, respectively. This study may provide important insights into the roles of negative regulators of OC differentiation in bone homeostasis and osteolytic bone diseases of excessive OC differentiation. Knowledge gained from this study may generate potential therapeutic targets, through characterization of Ga13 signaling in OCs that may be targeted in treating osteolytic bone diseases by mimicking normal OC inhibitory signaling pathway to control OC formation. A multidisciplinary research team, including a bone biologist with expertise in OC biology and animal models of bone diseases; a bone biologist with expertise in OC biology and cell signaling; and an immunologist with expertise in autoimmunity diseases including RA has been established to achieve the research goal.


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: 2023 ( Subtotal = $0 )
2023	2021	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	2/10/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
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	001	5	2/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
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	000	5	10/25/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $324,368 )
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	5	7/31/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$296,080
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	001	5	6/16/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$324,368
2021	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	4	7/31/2021	NON-COMPETING CONTINUATION	-$296,080
2021	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/15/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $324,368

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	4	5/5/2020	NON-COMPETING CONTINUATION	$326,700
														Subtotal = $326,700

Issue Date FY: 2019 ( Subtotal = $326,700 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/5/2019	NON-COMPETING CONTINUATION	$326,700
														Subtotal = $326,700

Issue Date FY: 2018 ( Subtotal = $326,700 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/17/2018	NON-COMPETING CONTINUATION	$326,700
														Subtotal = $326,700

Issue Date FY: 2017 ( Subtotal = $326,700 )
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	4/5/2017	NEW	$3,300
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/23/2017	NEW	$323,400
														Subtotal = $326,700

Grand Total All Awards = $1,631,168

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Characterizing the mechanism by which endogenous negative regulators of osteoclasts control bone homeostasis under physiological and pathological conditions in mouse models

Award Number: R01AR070135

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer