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SLC24A4 in enamel maturation, from expression to etiology

Award Number: F31DE035793
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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SLC24A4 in enamel maturation, from expression to etiology - PROJECT SUMMARY/ABSTRACT Tooth enamel is the hardest tissue in humans and its proper formation ensures the lifelong protection of the teeth from masticatory wear and tear. This high degree of mineralization is facilitated by the robust ion transporting capacity of ameloblasts, the architects of enamel. Ameloblasts express the SLC24A4 calcium transporter (solute carrier family 24 member 4) to efflux calcium into the developing enamel. Mutations in the SLC24A4 gene lead to severe enamel malformations, specifically hypomature and hypomineralized forms of amelogenesis imperfecta. Previous work has demonstrated that ameloblasts upregulate Slc24a4 in a stage-specific manner during enamel formation. Using a mouse model that lacks SLC24A4, our lab found that these animals recapitulated the human disease and formed hypomature enamel. Despite SLC24A4’s critical role in enamel development and its implications in enamel disease, there is still very little known regarding (1) the regulatory mechanisms that control its expression in enamel formation as well as (2) the precise cellular mechanisms driving AI upon SLC24A4 ablation. Our preliminary data has identified that transcription factors, RUNX2 and HIF1A, may regulate Slc24a4 expression. In mice lacking SLC24A4, protein abundance and subcellular localization were severely affected, coinciding with bulk-RNA seq analysis that revealed ER stress to be the most significant affected biological processes in Slc24a4-/- ameloblasts. Based on these preliminary data, I hypothesize that ameloblasts employ stage-specific transcriptional regulators to transactivate Slc24a4 in order to not only regulate enamel mineralization but to also protect against ER stress. I propose to use the following two aims to address this hypothesis: AIM 1: To identify mechanisms underlying the stage-specific expression and regulation of Slc24a4: ATAC-seq and H3K27ac CUT&RUN analyses of differentiating ameloblasts will be conducted to assess whether chromatin accessibility of the Slc24a4 regulatory region varies by stage. Direct binding of RUNX2 and HIF1A with the Slc24a4 gene regulatory region will be determined by CUT&RUN. AIM 2: To determine the extent SLC24A4 functions to protect against ER stress and its relation to AI: ER stress responses in Slc24a4-/- ameloblasts will be assessed by immunohistochemistry, qPCR, and western blotting. Whether proteins found to be disrupted in the Slc24a4-/- ameloblasts are targeted by the UPR will be determined by proximity ligation assay. Electron microscopy and immunogold labeling will examine the subcellular distribution and accumulation of proteins in the ER of Slc24a4-/- ameloblasts. Finally, challenge and rescue studies will be performed in vitro and in vivo to determine SLC24A4’s function in relation to ER stress. This fellowship will allow me to investigate how SLC24A4 contributes to enamel biomineralization and homeostasis in ameloblasts, fostering my pursuit of an academic career focused on enamel formation and identifying novel strategies to address the clinical needs of patients with enamel defects.


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 = $50,610 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	1	8/25/2026	NEW	$50,610
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	1	8/25/2026	NEW	$0
														Subtotal = $50,610

Grand Total All Awards = $50,610

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SLC24A4 in enamel maturation, from expression to etiology

Award Number: F31DE035793

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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