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Role and Mechanism of Action of Ksr2, an Obesity and Type 2 Diabetes Gene, in Bone Metabolism

Award Number: R01AR048139
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: 01/01/2003
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Role and Mechanism of Action of Ksr2, an Obesity and Type 2 Diabetes Gene, in Bone Metabolism - Abstract In an increasingly aging and obese population, type 2 diabetes (T2DM) and osteoporotic fractures are major public health concerns. Affecting more than 1 in 3 adults in the United States, obesity is the most important risk factor for T2DM. It is now well established that obesity and T2DM have effects on fracture risk, and fractures in T2DM are associated with greater morbidity than in the general population. Although bone density is generally known to be increased in obese and T2DM patients, the underpinning causes that contribute to increased fracture risk in T2DM/obese subjects remain to be established. Therefore, understanding the interactions of obesity, T2DM and fracture is becoming a pressing need to reduce the societal and individual costs of fracture. Our efforts to identify control molecules and their signaling pathways that delineate a link between T2DM, osteoporosis and obesity led to the exciting discovery that targeted disruption of kinase suppressor of Ras 2 (Ksr2), an obesity and T2DM gene, led to a >2-fold increase in trabecular bone mass at the distal femur of 4-month-old mice besides inducing obesity and T2DM. By contrast, disruption of a closely related Ksr1 gene had no significant effect on bone or obese phenotypes. KSR1 and 2 were discovered as scaffolding proteins that orchestrate the assembly of Raf, MEK and ERK in the canonical Ras-Raf-MAPKs pathway. While a central role for Ksr2 expressed in hypothalamus has been implicated in the control of feeding behavior and energy balance and, thereby obesity, we have new exciting preliminary data that suggest that KSR2 expressed in osteoblasts acts locally in a cell autonomous fashion to regulate its functions. Based on our preliminary data and published data, we propose a novel hypothesis that KSR2 regulates osteoblast differentiation and bone formation via regulating mTORC1 signaling and its downstream hypoxia signaling. In this competitive renewal RO1 application, we will test this model of KSR2 action as follows: 1) To test the hypothesis that KSR2 acts in a cell autonomous fashion to regulate trabecular bone formation, we will generate osteoblast-specific Ksr2 conditional knockout mice and characterize its skeletal phenotype by micro-CT, histology, mechanical testing and gene expression. 2) To test the hypothesis that KSR2 effects on osteoblasts are mediated via its regulation of mTORC1 signaling, we will determine the functional consequence of KSR2/mTORC1 pathway interactions by evaluating if knockdown of Raptor in osteoblasts abolishes the increased anabolic functions of Ksr2 knockdown osteoblasts. 3) To test the hypothesis that KSR2/mTORC1 effects on osteoblasts are mediated via HIF1α signaling, we will evaluate changes in hypoxia signaling in osteoblasts with conditional disruption of Ksr2 and/or Raptor. We will also determine if disruption of Hif1α expression in osteoblasts rescues the skeletal phenotype in osteoblast-specific Ksr2 conditional knockout mice. Successful completion of our proposed studies will provide important information on the pathway/s by which KSR2 regulates osteoblast and bone marrow adipocyte functions and could lead to improved understanding of the mechanisms linking obesity and a high bone mass phenotype.


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 = $312,631 )
2025	2025	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	16	12/20/2024	NON-COMPETING CONTINUATION	$290,070
2025	2025	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	16	6/12/2025	NON-COMPETING CONTINUATION	$22,561
														Subtotal = $312,631

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	000	15	12/7/2023	NON-COMPETING CONTINUATION	$290,070
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	15	6/10/2024	NON-COMPETING CONTINUATION	$22,561
														Subtotal = $312,631

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	001	14	5/12/2023	NON-COMPETING CONTINUATION	$32,230
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	14	1/20/2023	NON-COMPETING CONTINUATION	$290,070
														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	001	13	5/25/2022	NON-COMPETING CONTINUATION	$29,007
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	13	12/15/2021	NON-COMPETING CONTINUATION	$290,070
														Subtotal = $319,077

Issue Date FY: 2021 ( Subtotal = $322,300 )
2021	2021	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	12	1/8/2021	COMPETING CONTINUATION	$322,300
														Subtotal = $322,300

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2016	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	11	3/11/2020	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2016	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	11	1/4/2019	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	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	001	11	2/7/2017	EXTENSION WITH OR WITHOUT FUNDS	$193,629
2017	2015	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	10	2/7/2017	NON-COMPETING CONTINUATION	-$193,629
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $307,215 )
2016	2016	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH & ED	POST OFFICE BOX 11238	SAN BERNARDINO	CA	92423	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	7/20/2016	EXTENSION WITH OR WITHOUT FUNDS	$307,215
														Subtotal = $307,215

Issue Date FY: 2015 ( Subtotal = $307,215 )
2015	2015	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH & ED	POST OFFICE BOX 11238	SAN BERNARDINO	CA	92423	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	7/29/2015	NON-COMPETING CONTINUATION	$307,215
														Subtotal = $307,215

Issue Date FY: 2014 ( Subtotal = $301,071 )
2014	2014	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH & ED	POST OFFICE BOX 11238	SAN BERNARDINO	CA	92423	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	8/20/2014	NON-COMPETING CONTINUATION	$301,071
														Subtotal = $301,071

Issue Date FY: 2013 ( Subtotal = $291,854 )
2013	2013	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH & ED	POST OFFICE BOX 11238	SAN BERNARDINO	CA	92423	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	8/1/2013	NON-COMPETING CONTINUATION	$291,854
														Subtotal = $291,854

Issue Date FY: 2012 ( Subtotal = $307,215 )
2012	2012	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH & ED	POST OFFICE BOX 11238	SAN BERNARDINO	CA	92423	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	9/11/2012	COMPETING CONTINUATION	$307,215
														Subtotal = $307,215

Issue Date FY: 2010 ( Subtotal = $308,260 )
2010	2010	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH & ED	POST OFFICE BOX 11238	SAN BERNARDINO	CA	92423	SAN BERNARDINO	USA	Trans-NIH Recovery Act Research Support	001	6	7/30/2010	NON-COMPETING CONTINUATION	$308,260
2010	2009	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH & ED	POST OFFICE BOX 11238	SAN BERNARDINO	CA	92423	SAN BERNARDINO	USA	Trans-NIH Recovery Act Research Support	000	5	6/9/2010	COMPETING CONTINUATION	$0
														Subtotal = $308,260

Issue Date FY: 2009 ( Subtotal = $308,260 )
2009	2009	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH & ED	POST OFFICE BOX 11238	SAN BERNARDINO	CA	92423	SAN BERNARDINO	USA	Trans-NIH Recovery Act Research Support	000	5	8/6/2009	COMPETING CONTINUATION	$308,260
														Subtotal = $308,260

Issue Date FY: 2006 ( Subtotal = $215,367 )
2006	2006	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH & ED	POST OFFICE BOX 11238	SAN BERNARDINO	CA	92423	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	7/28/2006	NON-COMPETING CONTINUATION	$215,367
														Subtotal = $215,367

Issue Date FY: 2005 ( Subtotal = $252,801 )
2005	2005	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH & ED	POST OFFICE BOX 11238	SAN BERNARDINO	CA	92423	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	8/25/2005	NON-COMPETING CONTINUATION	$252,801
														Subtotal = $252,801

Issue Date FY: 2004 ( Subtotal = $252,801 )
2004	2004	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH & ED	POST OFFICE BOX 11238	SAN BERNARDINO	CA	92423	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/25/2004	NON-COMPETING CONTINUATION	$252,801
														Subtotal = $252,801

Issue Date FY: 2003 ( Subtotal = $283,943 )
2003	2003	LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH & ED	POST OFFICE BOX 11238	SAN BERNARDINO	CA	92423	SAN BERNARDINO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/17/2003	NEW	$283,943
														Subtotal = $283,943

Grand Total All Awards = $4,724,941

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Role and Mechanism of Action of Ksr2, an Obesity and Type 2 Diabetes Gene, in Bone Metabolism

Award Number: R01AR048139

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: 01/01/2003

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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