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Systems Genetics of Bone Regeneration

Award Number: R01AR079179
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Systems Genetics of Bone Regeneration - Project Summary: There are over 1 million cases of failed bone repair in the U.S. annually, resulting in substantial patient morbidity and societal costs. The genetic factors affecting bone repair are poorly understood because the field has been limited by having to rely on interrogating genes with known relevance for osteoporosis or other biological processes such as inflammation. These studies have identified only a handful of genes. In contrast, systems genetics studies of many phenotypes including skeletal traits such as bone mineral density have already identified multiple novel genetic variants that can be targeted for therapeutic intervention. Unfortunately, the study of bone repair in patients is not readily amenable to this approach because of the difficulty in enrolling patients in studies after the occurrence of the index event, great variability in injury types and lack of simple readouts to assess repair. These barriers can be overcome by using a model organism with a well-defined injury mechanism and simple readout to characterize the repair phenotype. Thus, we will use systems genetics to discover novel genes influencing intramembranous bone regeneration induced by marrow ablation in a mouse model. Intramembranous bone repair is integral to fracture healing, distraction osteogenesis, fixation of orthopedic and dental implants to the skeleton and repair of large defects caused by trauma or necessitated by resection of bone tumors. In Aim 1, we will perform the first genome-wide association study (GWAS) for bone repair by measuring the intramembranous bone regenerative response after marrow ablation in Diversity Outbred (N=1000) mice. We will identify genes responsible for bone regeneration quantitative trait loci (QTL) and expression QTL using multiple fine-mapping approaches and transcriptomic data generated from single cell RNA-seq. In Aim 2, we will use Bayesian networks and identify genes highly connected to known regulators of bone traits using Key Driver Analysis to identify candidate causal genes for the bone regenerative response. In Aim 3, we will validate the role of Periostin, a recently identified candidate gene, and at least one additional candidate identified in the first two aims. We will begin by testing the role of Periostin, a gene implicated in intramembranous bone regeneration in preliminary transcriptomic, lineage tracing and key driver analyses. The project will significantly increase our understanding of the genetics of bone repair. Genes that we identify will serve as potential therapeutic targets capable of improving multiple orthopedic and dental procedures which rely on bone repair.


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: 2026 ( Subtotal = $618,389 )
2026	2026	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/22/2026	NON-COMPETING CONTINUATION	$585,842
2026	2026	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	5/14/2026	NON-COMPETING CONTINUATION	$32,547
														Subtotal = $618,389

Issue Date FY: 2025 ( Subtotal = $657,939 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	2/19/2025	NON-COMPETING CONTINUATION	$610,459
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/9/2025	NON-COMPETING CONTINUATION	$47,480
														Subtotal = $657,939

Issue Date FY: 2024 ( Subtotal = $657,413 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/29/2024	NON-COMPETING CONTINUATION	$47,442
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/5/2024	NON-COMPETING CONTINUATION	$609,971
														Subtotal = $657,413

Issue Date FY: 2023 ( Subtotal = $699,266 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/19/2023	NON-COMPETING CONTINUATION	$629,340
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	4/24/2023	NON-COMPETING CONTINUATION	$69,926
														Subtotal = $699,266

Issue Date FY: 2022 ( Subtotal = $703,045 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	4/8/2022	NEW	$703,045
														Subtotal = $703,045

Grand Total All Awards = $3,336,052

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Systems Genetics of Bone Regeneration

Award Number: R01AR079179

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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