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Mechanistic basis of the role of Cbx3 in negatively regulating osteoclast differentiation through epigenetic modification

Award Number: R01AR075735
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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The long term goal of this study is to develop safer and effective therapeutic approach for bone loss caused by excessive osteoclast (OC) differentiation implicated in many metabolic bone diseases. The immediate goal of this application is to understand how OC differentiation is regulated through negative signaling mediated by transcription factors and epigenetic regulators, which may serve as novel therapeutic targets for bone diseases such as osteoporosis. Current therapies for osteolytic diseases are hindered by lack of understanding of the mechanisms underlying the negative regulation of OC function to prevent bone loss. Moreover, the mechanism(s) underlying how transcriptional factors and epigenetic factors co-regulate, especially negatively co-regulate, OC differentiation and function remain unclear. We have identified Cbx3/HP1¿. Our subsequent immunoprecipitation analysis confirmed that C/EBPa interacts with Cbx3/HP1¿ in OCs. Notably, our preliminary data showed that Cbx3/HP1¿ overexpression inhibited OC differentiation and activity, while Cbx3/HP1¿ silencing enhanced OC lineage commitment and formation. Consistently, Cbx3/HP1¿-deficient mice were found to exhibit osteoporosis-like phenotype due to enhanced OC formation and activity. Interestingly, through ChIP analysis, we found several binding sites of Cbx3/HP1¿ on the promoters of C/EBPa regulated OC genes, NFATC1 and C-FOS. Our RNA-seq analysis also revealed that Cbx3 deficiency in monocytes led to increased OC gene expression. Collectively, the preliminary data indicated that Cbx3 can restrict C/EBPa-mediated OC differentiation and activity. Based on our preliminary studies, we hypothesize that Cbx3 negatively regulates osteoclast differentiation through interacting with C/EBPa and epigenetic factors as a result of epigenetic modification and preventing osteoclast gene expression in bone homeostasis. We will test the hypothesis through three specific aims. In Aim 1, we examine the function of Cbx3 in OC differentiation, skeletal development and bone homeostasis under physiological and pathological conditions through characterization of the phenotypes and pathomechanism in two Cbx3 CKO mouse models through loss-of-function studies. In Aim 2, we determine the role of Cbx3 in OC differentiation, skeletal development and bone homeostasis under physiological and pathological conditions by characterizing the phenotypes and pathomechanism in Cbx3 conditional transgenic overexpression mice through gain-of-function approach. We define the molecular mechanism underlying how Cbx3 negatively regulates OC differentiation through interacting with C/EBPa and controlling epigenetic modification in Aim 3. The study will elucidate the mechanism(s) through which Cbx3 cooperates with transcriptional factors and other epigenetic factors to negatively regulate OC differentiation and activity. Insights gained from this study will not only address the basic scientific question about epigenetic regulation of gene expression in OC biology, but also will provide the foundation for the ultimate goal of facilitating the design of safer and novel therapeutic approach for osteolytic diseases (e.g. osteoporosis).


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 = $495,871 )
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	4	8/11/2023	NON-COMPETING CONTINUATION	$495,871
														Subtotal = $495,871

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	002	3	10/21/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$508,655
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	005	3	9/9/2022	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	003	3	10/25/2021	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	004	3	2/16/2022	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	001	2	10/21/2021	NON-COMPETING CONTINUATION	-$484,453
2022	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	10/21/2021	NEW	-$24,202
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $480,995 )
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	3	8/6/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$480,995
2021	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/5/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $480,995

Issue Date FY: 2020 ( Subtotal = $484,453 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/12/2020	NON-COMPETING CONTINUATION	$484,453
														Subtotal = $484,453

Issue Date FY: 2019 ( Subtotal = $484,453 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/6/2019	NEW	$484,453
														Subtotal = $484,453

Grand Total All Awards = $1,945,772

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Mechanistic basis of the role of Cbx3 in negatively regulating osteoclast differentiation through epigenetic modification

Award Number: R01AR075735

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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