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MATRIX BASED MINERAL ENAMEL-BIOMIMETICS

Award Number: R01DE013414
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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MATRIX BASED MINERAL ENAMEL-BIOMIMETICS - PROJECT SUMMARY/ABSTRACT The goal of this proposal is to provide insight into the structure, dynamic interactions and multifunctionality of the enamel protein ameloblastin (Ambn), and hence to contribute to the fundamental knowledge as relevant to enamel biomineralization. Ambn is multifunctional with critical roles in the regulation of mineral formation, cell differentiation, cell polarization, and cell–matrix adhesion. We recently identified a novel, highly-conserved amphipathic helix (AH) cell binding domain, located within the sequence encoded by exon 5, and adjacent to the C-terminus of the well-established Ambn self-assembly/co-assembly domain. Our preliminary data using two novel CRISPR-Cas9 gene editing mouse models in which different parts of the AH domain are deleted, show that the AH plays essential roles in amelogenesis. Analysis of enamel from homozygous strains with different deletion mutations on AH domain revealed distinct enamel phenotypes that exhibited hypomineralization with different severity. These observations along with recent published reports from our laboratory have led us to hypothesize that Ambn is a matricellular protein, and its complex role in amelogenesis relies on a multitargeting property centered in the region of the sequence encoded by exon 5. Ambn interacts with ameloblast cells via the AH domain and functions to anchor the mineralizing extracellular matrix to enamel-forming cells. To test our hypothesis, we seek to implement a mechanistic approach to interrogate the structure and function of the multitargeting motif in Ambn, including the AH domain. This will be achieved by 1) conducting a detailed investigation of enamel formation in two novel Ambn AH mutant mouse models in vivo (Aim I), 2) examining Ambn-cell interactions in 3-D cell culture (Aim II), and 3) completing an in vitro investigation of interacting domains in the Ambn sequence involved in its self-assembly, amelogenin (Amel), other potential targets, and cell membrane interactions (Aim III). Overall, our studies will advance understanding of the molecular function of Ambn in enamel biomineralization and of inherited enamel disease, elucidate genetic factors leading to caries susceptibility, and contribute to our efforts to regenerate dental hard tissues.


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 = $520,752 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Oral Diseases and Disorders Research	003	19	5/8/2025	NON-COMPETING CONTINUATION	$52,076
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	19	4/17/2025	NON-COMPETING CONTINUATION	$468,676
2025	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	18	1/15/2025	COMPETING CONTINUATION	$264,278
2025	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	17	1/15/2025	NON-COMPETING CONTINUATION	-$264,278
														Subtotal = $520,752

Issue Date FY: 2024 ( Subtotal = $523,857 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	18	7/1/2024	COMPETING CONTINUATION	$523,857
														Subtotal = $523,857

Issue Date FY: 2022 ( Subtotal = $405,031 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	17	4/29/2022	NON-COMPETING CONTINUATION	$36,825
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	17	4/13/2022	NON-COMPETING CONTINUATION	$368,206
														Subtotal = $405,031

Issue Date FY: 2021 ( Subtotal = $409,121 )
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	16	4/29/2021	NON-COMPETING CONTINUATION	$409,121
														Subtotal = $409,121

Issue Date FY: 2020 ( Subtotal = $778,388 )
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	15	4/10/2020	NON-COMPETING CONTINUATION	$461,517
2020	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	14	1/12/2020	COMPETING CONTINUATION	$316,871
														Subtotal = $778,388

Issue Date FY: 2019 ( Subtotal = $421,706 )
2019	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	14	3/28/2019	COMPETING CONTINUATION	$461,774
2019	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	13	2/3/2019	EXTENSION WITH OR WITHOUT FUNDS	-$40,068
														Subtotal = $421,706

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	13	9/17/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
2018	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	13	5/7/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	13	2/4/2017	EXTENSION WITH OR WITHOUT FUNDS	$52,374
2017	2015	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	12	2/4/2017	NON-COMPETING CONTINUATION	-$52,374
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $412,500 )
2016	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	13	5/11/2016	EXTENSION WITH OR WITHOUT FUNDS	$412,500
														Subtotal = $412,500

Issue Date FY: 2015 ( Subtotal = $387,796 )
2015	2015	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	12	5/13/2015	NON-COMPETING CONTINUATION	$387,796
														Subtotal = $387,796

Issue Date FY: 2014 ( Subtotal = $386,804 )
2014	2014	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	11	6/11/2014	NON-COMPETING CONTINUATION	$386,804
														Subtotal = $386,804

Issue Date FY: 2013 ( Subtotal = $401,067 )
2013	2013	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	10	6/13/2013	COMPETING CONTINUATION	$401,067
2013	2011	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	9	12/18/2012	NON-COMPETING CONTINUATION	$0
2013	2011	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	9	6/12/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $401,067

Issue Date FY: 2012 ( Subtotal = $0 )
2012	2009	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Trans-NIH Recovery Act Research Support	000	7	7/27/2012	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2011 ( Subtotal = $375,409 )
2011	2011	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	9	12/30/2010	NON-COMPETING CONTINUATION	$348,316
2011	2011	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	9	5/16/2011	NON-COMPETING CONTINUATION	$27,093
2011	2009	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Trans-NIH Recovery Act Research Support	002	7	7/11/2011	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $375,409

Issue Date FY: 2010 ( Subtotal = $537,726 )
2010	2010	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	8	12/11/2009	NON-COMPETING CONTINUATION	$351,835
2010	2010	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	8	1/12/2010	NON-COMPETING CONTINUATION	$35,182
2010	2009	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Trans-NIH Recovery Act Research Support	001	7	1/4/2010	SUPPLEMENT FOR EXPANSION	$150,709
														Subtotal = $537,726

Issue Date FY: 2009 ( Subtotal = $554,367 )
2009	2009	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Trans-NIH Recovery Act Research Support	004	7	9/1/2009	SUPPLEMENT FOR EXPANSION	$166,338
2009	2009	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	7	2/3/2009	NON-COMPETING CONTINUATION	$341,890
2009	2009	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Trans-NIH Recovery Act Research Support	003	7	6/2/2009	SUPPLEMENT FOR EXPANSION	$8,150
2009	2009	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	7	2/24/2009	NON-COMPETING CONTINUATION	$0
2009	2009	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	7	3/24/2009	NON-COMPETING CONTINUATION	$37,989
														Subtotal = $554,367

Grand Total All Awards = $8,356,388

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MATRIX BASED MINERAL ENAMEL-BIOMIMETICS

Award Number: R01DE013414

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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