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Mechanisms regulating Dock7-dependent osteoblast mobility and bone formation

Award Number: F32AR067071
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2015
PERIOD OF PERFORMANCE END DATE: 07/31/2018

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Mechanisms regulating Dock7-dependent osteoblast mobility and bone formation - ¿ DESCRIPTION (provided by applicant): Osteoporosis is caused by the uncoupling of bone formation and bone resorption, resulting in low bone mass. Osteoporotic fractures are costly in terms of health care dollars and quality of life due to higher mortality and morbidity. Most osteoporosis therapies stabilize bone mass through inhibition of bone resorption; however, stimulation of bone formation may prove a more beneficial approach to reverse bone loss. A greater understanding of factors regulating the bone formation process holds promise for new therapeutics to treat osteoporosis and prevent bone loss. Recent studies have identified that global loss of Dedicator of cytokinesis 7 (Dock7), a guanine nucleotide exchange factor (GEF), in the spontaneous Dock7 mutant, the Misty mice, results in low bone mass with suppressed bone formation and accelerated bone resorption. Furthermore, preliminary data demonstrate that osteoblast precursors in Misty mice have defects in cell mobility, decreased cell migration and increased cell adhesion, as well as impaired osteogenic differentiation. Activation of small GTPases such as Rac1 and Cdc42, known targets of Dock7 as well as integral components of integrin and Wnt signaling pathways are important for modulators of osteoblast mobility and differentiation. Although the low bone mass phenotype observed in the Misty mice is in part due to higher sympathetic outflow, in vitro data support the working hypothesis that Dock7 is a critical regulator of osteoblast mobility and differentiation. In order to test that hypothesis, tw specific aims are proposed: (1) Define the role of Dock7 in controlling cell mobility and osteogenic differentiation of osteoblast precursors through modulation of small GTPase activation in integrin and Wnt signaling pathways; (2) Investigate the mechanism by which Dock7 controls bone remodeling in vivo through skeletal phenotyping of the conditional and global Dock7 knockout mice. By deleting Dock7 in mesenchymal stem cells using Prx1-Cre, the requirement for Dock7 in the formation of normal bone mass and coupling of bone remodeling can be assessed. The work proposed here will define the mechanism by which Dock7 regulates osteoblast differentiation and function and will provide new insights into potential therapeutic targets to combat osteoporosis. Through a combination of multidisciplinary mentoring, a thorough scientific investigation, utilizing primary in vitro culture and in vivo models, participaion in scientific meetings, focused instruction in manuscript and grant writing, and education on research ethics, these studies and the training plan will prepare the applicant for a nationally competitive and independent career in basic and translational bone biology research.


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: 2022 ( Subtotal = $0 )
2022	2017	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	9/21/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2017	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	12/31/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $67,617 )
2017	2017	MAINE MEDICAL CENTER	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/18/2017	NON-COMPETING CONTINUATION	$67,617
														Subtotal = $67,617

Issue Date FY: 2016 ( Subtotal = $63,750 )
2016	2016	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/13/2016	NON-COMPETING CONTINUATION	$63,750
														Subtotal = $63,750

Issue Date FY: 2015 ( Subtotal = $58,802 )
2015	2015	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	7/13/2015	NEW	$58,802
2015	2015	MAINE MEDICAL CENTER	22 BRAMHALL STREET	PORTLAND	ME	04102	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/13/2015	NEW	$0
														Subtotal = $58,802

Grand Total All Awards = $190,169

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Mechanisms regulating Dock7-dependent osteoblast mobility and bone formation

Award Number: F32AR067071

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2015

PERIOD OF PERFORMANCE END DATE: 07/31/2018

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