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Molecular Mechanisms of LRRK1 Regulation of Bone Homeostasis

Award Number: R01AR078843
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: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Molecular Mechanisms of LRRK1 Regulation of Bone Homeostasis - Project Summary/Abstract Leucine rich repeat kinase 1 (LRRK1), a novel serine/threonine kinase, is expressed in bones, brain and other tissues. We recently demonstrated that Lrrk1 gene knockout (KO) mice as well as a patient with a Lrrk1 gene mutation are severely osteopetrotic due to osteoclast dysfunction and reduced bone resorption in long and vertebra bones. More importantly, Lrrk1 KO mice had lifelong bone accumulation and responded normally to the anabolic actions of teriparatide treatment but were resistant to ovariectomy (OVX)-induced bone boss. These observations make LRRK1 an ideal target of a novel anti-resorption drugs for treatment of osteoporosis. In this grant, our focus is to perform in vivo and in vitro studies to study the role of LRRK1-mediated phosphorylation of osteopetrosis specific transmembrane protein 1 (OSTM1) in the regulation of chloride channel 7 (CLC7) complex stabilization, lysosomal peripheral movement, lysosomal acid secretion and OC function. To this end, we hypothesize that LRRK1 phosphorylation of OSTM1 at residues of threonine 328 and serine 329 regulates OC function and bone resorption by stabilization of OSTM1/CLC7 complex and promotion of lysosomal peripheral movement and lysosomal acid secretion into lacuna in vivo. Four-year studies proposed in this grant will deliver the role of LRRK1 phosphorylation of threonine and serine residues of OSTM1 in regulation of bone resorption in vitro and in vivo. The results of this application will help our understanding of molecular mechanisms of LRRK1 and OSTM1 actions in osteoclast and develop potential inhibitors of LRRK1 for treatment of osteoporosis in future.


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 = $0 )
2025	2024	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH AND EDUCATION	25884 BUSINESS CENTER DR	REDLANDS	CA	92374	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $312,631 )
2024	2024	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH AND EDUCATION	25884 BUSINESS CENTER DR	REDLANDS	CA	92374	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	6/7/2024	NON-COMPETING CONTINUATION	$22,561
2024	2024	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH AND EDUCATION	25884 BUSINESS CENTER DR	REDLANDS	CA	92374	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	12/7/2023	NON-COMPETING CONTINUATION	$290,070
														Subtotal = $312,631

Issue Date FY: 2023 ( Subtotal = $322,300 )
2023	2023	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH AND EDUCATION	25884 BUSINESS CENTER DR STE A	REDLANDS	CA	92374	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/22/2022	NON-COMPETING CONTINUATION	$290,070
2023	2023	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH AND EDUCATION	25884 BUSINESS CENTER DR	REDLANDS	CA	92374	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/12/2023	NON-COMPETING CONTINUATION	$32,230
														Subtotal = $322,300

Issue Date FY: 2022 ( Subtotal = $322,300 )
2022	2022	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH AND EDUCATION	25884 BUSINESS CENTER DR STE A	REDLANDS	CA	92374	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	12/30/2021	NEW	$322,300
														Subtotal = $322,300

Grand Total All Awards = $957,231

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Molecular Mechanisms of LRRK1 Regulation of Bone Homeostasis

Award Number: R01AR078843

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: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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