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Studies of Osteoclast Lineage in Health and Diseases

Award Number: R01AR077534
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: 06/23/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Studies of Osteoclast Lineage in Health and Diseases - Although, we know much about the molecular signals that regulate OC function, we know relatively little about the lineage and mechanisms that OC use to develop from progenitors. The goal of this application is to better define OC progenitor (OCP) maturation and trafficking and the mechanisms regulating this process in health and disease so that we can identify potential drug targets to develop superior therapies for bone diseases. The central hypotheses are: 1) During homeostasis marrow-resident cells are the principal OCP source, while during inflammation or fracture repair, circulating cells become a significant source of OCP. 2) The mechanisms regulating OCP migration, engraftment and maturation to OC in bone differ between healthy and disease states. To test these hypotheses, we propose the following aims: 1. Define the role that CX3CR1+ OCP have in OC development during homeostasis and identify mechanisms regulating their homing, engraftment and maturation to OC: 1A) Perform time course studies in CX3CR1-CreERT2-Ai14 mice at various ages to examine labeled OC formation kinetics. We will also monitor the kinetics of labeled OCP in the bone marrow, blood and spleen. 1B) The chemokine receptor CX3CR1 is expressed on OCP and has previously been implicated to influence OCP homing, engraftment and maturation. We will determine its role in OCP lineage development and trafficking in vivo under homeostatic conditions (when marrow-derived cells predominate as the OCP source) using CX3CR1-CreERT2-Ai14 mice to generate Cx3cr1 gene deletions. 2. Examine OCP homing from the circulation during bone inflammation and fracture repair. These studies will examine two disease models in which we previously demonstrated that circulating OCP are recruited to engraft in bone: TNFa-induced bone inflammation and a repairing fracture. 2A) Study a TNFa-induced inflammatory bone model (a WT parabiont has TNFα injected over its calvaria; the other parabiont is a CX3CR1-EGFP; TRAP-tdTomato mouse) and determine the rate that circulating labeled cells home to the inflammatory site, form OC and disappear. 2B) Study a parabiosis fracture model (a WT parabiont receives a femur fracture; the other parabiont is a CX3CR1-EGFP; TRAP-tdTomato mouse) and determine the rate that circulating labeled cells home to the repairing callus, form OC and disappear. 2C) Determine the phenotype and kinetics of circulating OCP that home, mature and engraft in bone with TNFa-induced inflammation or fracture repair by injecting selected populations of OCP from CX3CR1-EGFP; TRAP-tdTomato mice and monitoring the rates that labeled OC appear and disappear in bone. 2D) Determine the effect that deletion of Cx3cr1 has on the ability of circulating OCP to home, engraft and mature in bone with TNFa-induced inflammation or a fracture repair using parabiosis and adoptive transfer.


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: 2025 ( Subtotal = $429,260 )
2025	2025	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	6/4/2025	NON-COMPETING CONTINUATION	$30,978
2025	2025	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	12/4/2024	NON-COMPETING CONTINUATION	$398,282
														Subtotal = $429,260

Issue Date FY: 2024 ( Subtotal = $425,998 )
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/10/2024	NON-COMPETING CONTINUATION	$30,743
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	12/8/2023	NON-COMPETING CONTINUATION	$395,255
														Subtotal = $425,998

Issue Date FY: 2023 ( Subtotal = $435,905 )
2023	2023	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/6/2023	NON-COMPETING CONTINUATION	$43,591
2023	2023	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	11/14/2022	NON-COMPETING CONTINUATION	$392,314
														Subtotal = $435,905

Issue Date FY: 2022 ( Subtotal = $428,406 )
2022	2022	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/4/2022	NON-COMPETING CONTINUATION	$38,946
2022	2022	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/3/2021	NON-COMPETING CONTINUATION	$389,460
														Subtotal = $428,406

Issue Date FY: 2021 ( Subtotal = $214,827 )
2021	2021	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/23/2021	NEW	$214,827
2021	2021	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	6/24/2021	NEW	$0
														Subtotal = $214,827

Grand Total All Awards = $1,934,396

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Studies of Osteoclast Lineage in Health and Diseases

Award Number: R01AR077534

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: 06/23/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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