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Identifying Osteoporosis Genes by Whole Genome Sequencing and Functional Validation in Zebra Fish

Award Number: R01AR072199
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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Project Summary/Abstract Osteoporosis has become a major and growing worldwide public health burden. Due to fears of side effects, the use of osteoporosis drugs has fallen by as much as 50%. Thus, there is an unmet need to develop new drugs for osteoporosis; or to develop personalized therapeutic approaches with the ability to takes into account individual variability for each patient. Using human genetic studies to identify new druggable targets should overcome the current treatment crisis in osteoporosis. Although GWAS have been successful in discovering associated genetic variants with complex traits, more than 88% of GWAS loci are non-coding, which makes the identification of causal variants and their targeted genes a difficult challenge; thus, limits the use of human genetics information in drug discovery. To overcome these challenges and get better understanding of GWAS findings, we proposed to utilize whole genome sequencing in large well-phenotyped populations as well as the CRISPR/Cas9 gene-editing zebrafish model to identify potential causal variants and targeted genes influencing skeletal integrity. Our findings may eventually lead to new diagnostics and therapeutics of osteoporosis. We proposed three specific aims, including: 1) Fine-map previous BMD GWAS loci by existing WGS in 10,000 individuals from the Trans-Omics for Precision Medicine (TOPMed) Program to identify potential causal sequence variants (functional variants) that are responsible for GWAS signals; 2) Identify novel structural variation and novel rare sequence variants associated with BMD by performing a whole genome scan using the same 10,000 WGS samples. We will replicate findings in an additional 5,000 samples selected from the GENOMOS/GEFOS consortium; 3) Functionally characterize up to 30 genes selected from aims 1 and 2 in knockout zebrafish by CRISPR/Cas9 gene-editing systems. State-of-the-art technologies for rapid phenotyping in zebrafish will be applied to a broad range of physiologies (skeletal development, ontogenesis, and regeneration) and characteristics (bone mass accrual, morphology, and mineral density). Our proposal is fundamentally important and represents the logical next step in skeletal genetics research. The results will lead to much needed new drug development to overcome the growing treatment gap in 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: 2024 ( Subtotal = $0 )
2024	2022	HEBREW REHABILITATION CENTER	1200 CENTRE ST	ROSLINDALE	MA	02131	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	7/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	HEBREW REHABILITATION CENTER	1200 CENTRE ST	ROSLINDALE	MA	02131	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	9/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $412,787 )
2022	2022	HEBREW REHABILITATION CENTER FOR AGED, INC.	1200 CENTRE ST	BOSTON	MA	02131	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	9/19/2022	NON-COMPETING CONTINUATION	$412,787
														Subtotal = $412,787

Issue Date FY: 2021 ( Subtotal = $694,650 )
2021	2021	HEBREW REHABILITATION CENTER FOR AGED, INC.	1200 CENTRE ST	BOSTON	MA	02131	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	7/15/2021	NON-COMPETING CONTINUATION	$694,650
														Subtotal = $694,650

Issue Date FY: 2020 ( Subtotal = $731,324 )
2020	2020	HEBREW REHABILITATION CENTER FOR AGED, INC.	1200 CENTRE ST	BOSTON	MA	02131	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	8/19/2020	NON-COMPETING CONTINUATION	$731,324
2020	2018	HEBREW REHABILITATION CENTER FOR AGED, INC.	1200 CENTRE ST	BOSTON	MA	02131	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	11/18/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $731,324

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	HEBREW REHABILITATION CENTER FOR AGED, INC.	1200 CENTRE ST	BOSTON	MA	02131	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	9/26/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $740,722 )
2018	2018	HEBREW REHABILITATION CENTER FOR AGED, INC.	1200 CENTRE ST	BOSTON	MA	02131	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	9/8/2018	NON-COMPETING CONTINUATION	$740,722
2018	2017	HEBREW REHABILITATION CENTER FOR AGED, INC.	1200 CENTRE ST	BOSTON	MA	02131	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/7/2018	NEW	$0
														Subtotal = $740,722

Issue Date FY: 2017 ( Subtotal = $592,021 )
2017	2017	HEBREW REHABILITATION CENTER FOR AGED, INC.	1200 CENTRE ST	BOSTON	MA	02131	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/31/2017	NEW	$592,021
														Subtotal = $592,021

Grand Total All Awards = $3,171,504

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Identifying Osteoporosis Genes by Whole Genome Sequencing and Functional Validation in Zebra Fish

Award Number: R01AR072199

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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