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Canonical Wnt Signaling as a Novel Regulator of Chondrocyte to Osteoblast Transdifferentiation during Endochondral Bone Repair in the Mandible

Award Number: F30DE026359
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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PROJECT SUMMARY / ABSTRACT There are approximately 15 million bone fractures annually and the mandible sustains the majority of fractures of the craniofacial skeleton. Importantly, prevalence of impaired healing is significant and remains an unmet clinical need. Understanding the mechanisms that direct fracture healing is imperative to the development of improved therapies. The mandible heals through the process of endochondral ossification, in which a cartilage intermediate forms and is later replaced by bone. Recent work has revealed a new model of endochondral ossification in which chondrocytes of the cartilage intermediate transdifferentiate into osteoblasts that form the new bone at a region adjacent to the invading vasculature. The mechanisms underlying chondrocyte transdifferentiation have not been explored, but my preliminary data, along with previously published work, indicate that canonical Wnt signaling may be a central mediator of chondrocyte transdifferentiation. For this project I aim to understand the role of canonical Wnt signaling during endochondral bone repair, and then test the therapeutic effect of a novel, water-soluble molecule that strongly activates Wnt signaling. The central hypothesis for this project is that canonical Wnt signaling regulates chondrocyte transdifferentiation by inducing the osteogenic program and that activation of the Wnt pathway through administration of Wnt-Surrogate accelerates mandible fracture healing by increasing the rate of conversion of chondrocytes to osteoblasts. To determine the role of canonical Wnt signaling during endochondral fracture repair, in my first Aim, I will use transgenic mouse strains to conditionally inhibit or activate canonical Wnt signaling in chondrocytes comprising the fracture callus. I will assess the effects of Wnt signaling on chondrocyte transdifferentiation by measuring the rate of cartilage to bone conversion. The effect of Wnt signaling on cellular re-programming will be determined by measuring the expression levels and patters of chondrogenic and osteogenic genes in chondrocytes using qPCR, in situ hybridization, immunohistochemistry, and stereology. In the second Aim, I will test the therapeutic effect of a novel surrogate Wnt ligand to promote fracture repair. The Garcia Laboratory (Stanford) has kindly provided us with the Wnt-Surrogate that strongly activates Wnt signaling in vitro. To determine the osteogenic effects of Wnt-surrogate, cartilage explants will be assessed for matrix mineralization and alkaline phosphatase activity in vitro. Additionally, mandible fracture models will be assessed for bone mineral density and rate of healing. Design of Experiments (DOE) methodologies will be used to optimize the dose and timing of Wnt-Surrogate administration, which will be applied to further in vivo analysis of the effect of Wnt-Surrogate on biomechanical strength and rate of bone formation. Taken together this study will provide improtant information regarding the role of canonical Wnt signaling in chondrocyte transdifferentiation and pre-clinical evidence for Wnt-Surrogate as a novel approach to fracture healing.


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: 2023 ( Subtotal = -$17,804 )
2023	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	6	5/15/2023	NON-COMPETING CONTINUATION	-$17,804
														Subtotal = -$17,804

Issue Date FY: 2021 ( Subtotal = $51,836 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	6	5/25/2021	NON-COMPETING CONTINUATION	$51,836
2021	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	5	1/15/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $51,836

Issue Date FY: 2020 ( Subtotal = $51,320 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	5	5/6/2020	NON-COMPETING CONTINUATION	$51,320
														Subtotal = $51,320

Issue Date FY: 2019 ( Subtotal = $50,816 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	4	5/22/2019	NON-COMPETING CONTINUATION	$50,816
														Subtotal = $50,816

Issue Date FY: 2018 ( Subtotal = $50,324 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	3	5/10/2018	NON-COMPETING CONTINUATION	$480
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	3	5/7/2018	NON-COMPETING CONTINUATION	$49,844
														Subtotal = $50,324

Issue Date FY: 2017 ( Subtotal = $40,252 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	2	5/29/2017	NON-COMPETING CONTINUATION	$39,784
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	2	6/29/2017	NON-COMPETING CONTINUATION	$468
														Subtotal = $40,252

Issue Date FY: 2016 ( Subtotal = $39,240 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	1	5/13/2016	NEW	$39,240
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	1	5/13/2016	NEW	$0
														Subtotal = $39,240

Grand Total All Awards = $265,984

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Canonical Wnt Signaling as a Novel Regulator of Chondrocyte to Osteoblast Transdifferentiation during Endochondral Bone Repair in the Mandible

Award Number: F30DE026359

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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