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Redox and Ca2+ signaling regulation of enamel mineralization

Award Number: R01DE027679
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: 03/10/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2028

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Redox and Ca2+ signaling regulation of enamel mineralization - Project Summary: Proper mineralization of dental enamel protects against bacterial attack that causes tooth decay (caries). The ameloblasts cells are responsible for producing and secreting an abundance of proteins (laying a foundation for enamel growth) as well as engaging in active mineral transport (calcifying the enamel). These functions are stage dependent with amelogenesis being divided into the secretory (protein synthesis) and maturation stage (mineralization). However, the mechanisms providing metabolic support for these processes and how mitochondrial dysfunction might alter them is poorly understood. Mitochondria are organelles within the cells that convert nutrients into energy via the production of ATP, and deficiency in mitochondrial function results in human diseases. Mitochondria play an important role in enamel as evidenced by defects in mitochondrial DNA causing abnormal enamel development. Therefore, the goal in this competing renewal proposal is to investigate the interplay between mitochondrial function and enamel formation during environmental insults and determine whether this is altered in patients with genetic disorders that effect mitochondrial function. We will specifically address this in the context of Down syndrome (DS), or Trisomy 21, and during dental fluorosis, a process in which exposure to excess of fluoride during development weakens tooth enamel. DS patients present with enamel defects including hypocalcification and hypoplasia, both caused by developmental defects in enamel formation. Mitochondrial dysfunction is widely reported in DS. The overarching hypothesis of this proposal is that altered mitochondrial function in DS ameloblasts alters enamel crystal formation and impacts sensitivity to fluorosis. In strong support, our preliminary data show that Dp- 16 mice (an established mouse model of DS) have mechanically weak and morphologically abnormal enamel. Moreover, overexpression of RCAN1 (a gene associated with DS pathophysiology that is expressed in ameloblasts) in enamel cell lines, significantly impaired mitochondrial function. We have also reported that fluoride exposure of enamel cells significantly affected the biosynthesis of the proteins of the electron transport chain (ETC) responsible for maintaining ATP production, but not in other cells tested, suggesting unique sensitivity of enamel cells to fluoride, possibly associated with higher ROS levels. In the proposed studies we will use DS mouse models (Dp16 mice, Rcan1-KO mice, Dp16 x Rcan1-KO mice) to address the role of mitochondria in the ameloblasts of these mice. We will also use recently developed reporter mice expressing fluorescently labelled secretory and maturation stage ameloblasts to induce fluoride and investigate mitochondrial defects using single cell RNASeq and bulk RNAseq to compare ameloblasts with other tissues. To address if ameloblasts of DS models are more sensitive to fluoride, we will treat the cells with fluoride and analyze mitochondrial function.


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: 2026 ( Subtotal = $456,923 )
2026	2026	NEW YORK UNIVERSITY	70 WASHINGTON SQ S FL 11	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	000	8	3/3/2026	NON-COMPETING CONTINUATION	$456,923
														Subtotal = $456,923

Issue Date FY: 2025 ( Subtotal = $469,362 )
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	002	7	5/7/2025	NON-COMPETING CONTINUATION	$46,936
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	001	7	2/28/2025	NON-COMPETING CONTINUATION	$422,426
2025	2021	NEW YORK UNIVERSITY	70 WASHINGTON SQ S FL 11	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	000	4	1/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $469,362

Issue Date FY: 2024 ( Subtotal = $459,975 )
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	000	6	5/28/2024	NON-COMPETING CONTINUATION	$459,975
														Subtotal = $459,975

Issue Date FY: 2023 ( Subtotal = $483,968 )
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	001	5	3/10/2023	COMPETING CONTINUATION	$483,968
2023	2021	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	000	4	3/2/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $483,968

Issue Date FY: 2021 ( Subtotal = $356,037 )
2021	2021	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	000	4	5/25/2021	NON-COMPETING CONTINUATION	$356,037
														Subtotal = $356,037

Issue Date FY: 2020 ( Subtotal = $357,772 )
2020	2020	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	000	3	5/8/2020	NON-COMPETING CONTINUATION	$357,772
														Subtotal = $357,772

Issue Date FY: 2019 ( Subtotal = $361,751 )
2019	2019	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	000	2	5/16/2019	NON-COMPETING CONTINUATION	$361,751
														Subtotal = $361,751

Issue Date FY: 2018 ( Subtotal = $361,751 )
2018	2018	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	000	1	9/14/2018	NEW	$361,751
														Subtotal = $361,751

Grand Total All Awards = $3,307,539

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Redox and Ca2+ signaling regulation of enamel mineralization

Award Number: R01DE027679

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: 03/10/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2028

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