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Role and Mechanism of Claudin-11 Action and Signaling in Bone

Award Number: R01AR070806
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: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Role and Mechanism of Claudin-11 Action and Signaling in Bone - Project Summary/Abstract Osteoporosis is a significant public health problem in the U.S. and poses a substantial financial burden. The pathogenesis of osteoporosis is known to involve increased destruction of bone, not compensated by parallel increases in the synthesis of new tissue. The only approved anabolic drug for osteoporosis, PTH, also increases bone resorption, thereby limiting its long term use. Thus, there is an urgent need for development of novel anabolic therapies for the treatment of osteoporosis. In our effort to identify control molecules and their signaling pathways that contribute to the regulation of osteogenesis, we have discovered a novel role for the Claudin (Cldn) family of tight junction proteins. In this RO1 application, our focus is on elucidating the role and mechanism of action of Cldn11 in regulating functions of osteoblasts (OBs) based on our exciting new data that mice with targeted disruption of the Cldn11 gene exhibit a severe deficit in trabecular bone volume (40%). Additionally, Cldn11 expression is increased several-fold during fracture healing. While the traditional role of Cldns is to regulate paracellular transport of small molecules, we have new exciting preliminary data that suggests that Cldn11 acts on OBs non-canonically via interacting with a transmembrane protein, Tetraspanin3 (Tspan3), to regulate ADAM10-mediated Notch signaling. We will test this model of Cldn11 action as follows: 1) To test the hypothesis that the Cldn11 expressed in OBs regulates trabecular bone formation, we will characterize the skeletal phenotype of OB-specific Cldn11 transgenic (Tg) mice by micro-CT, histology, mechanical testing and gene expression and determine if the reduced bone formation in Cldn11 KO mice can be rescued by transgenic expression of Cldn11 in OBs. 2) To test the hypothesis that Cldn11 effects on OBs are mediated via its interaction with Tspan3, we will determine the functional consequence of Cldn11/Tspan3 interactions by evaluating if knockdown of Tspan3 abolishes Cldn11-mediated differentiation in OBs, in vitro and in vivo. 3) To test the hypothesis that Cldn11/Tspan3 effects on OBs are mediated via ADAM10-mediated regulation of Notch signaling, we will evaluate the consequence of disruption of the Cldn11/Tspan3 interaction on ADAM10 maturation and activity via overexpression of a dominant negative mutant Cldn11 encoding the Tspan3 binding domain and determine if the Cldn11/Tspan3 interaction regulates Notch signaling and OB differentiation via modulation of ADAM10 activity. 4) To test the hypothesis that Cldn11 promotes fracture healing via regulating Notch signaling, we will determine the fracture phenotype in Cldn11 Tg and/or Tspan3 KO and control mice using a stabilized closed femoral fracture model. We will use notch signaling reporter mice to evaluate if Notch signaling is activated at the fracture site in the Cldn11 Tg mice and determine if treatment with an ADAM10 inhibitor blocks activated Notch signaling. Successful completion of our proposed studies will provide important information on the pathway by which Cldn11 regulates OB functions and could provide novel drug targets to promote anabolic activities of OBs for treatment of 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: 2025 ( Subtotal = $0 )
2025	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	000	5	1/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $322,300 )
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	000	5	7/7/2023	NON-COMPETING CONTINUATION	$322,300
														Subtotal = $322,300

Issue Date FY: 2022 ( Subtotal = $319,077 )
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	4	8/5/2022	NON-COMPETING CONTINUATION	$319,077
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	001	4	8/12/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $319,077

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	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	3	7/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	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	3	7/17/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $322,300 )
2019	2019	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH AND EDUCATION	710 BROOKSIDE AVE STE 2	REDLANDS	CA	92373	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/9/2019	NON-COMPETING CONTINUATION	$322,300
														Subtotal = $322,300

Issue Date FY: 2018 ( Subtotal = $322,300 )
2018	2018	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH AND EDUCATION	710 BROOKSIDE AVE STE 2	REDLANDS	CA	92373	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/14/2018	NON-COMPETING CONTINUATION	$322,300
														Subtotal = $322,300

Issue Date FY: 2017 ( Subtotal = $322,300 )
2017	2017	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH AND EDUCATION	710 BROOKSIDE AVE STE 2	REDLANDS	CA	92373	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/1/2017	NEW	$322,300
														Subtotal = $322,300

Grand Total All Awards = $1,608,277

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Role and Mechanism of Claudin-11 Action and Signaling in Bone

Award Number: R01AR070806

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: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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