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Mapping the developmental effects of TBCK loss in dental and craniofacial mineralization

Award Number: K08DE035951
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/06/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Mapping the developmental effects of TBCK loss in dental and craniofacial mineralization - PROJECT SUMMARY TBC1 Domain-Containing Kinase (TBCK) Syndrome is a devastating pediatric neurodevelopmental disorder caused by bi-allelic mutations in the TBCK gene. Affected children experience profound hypotonia, seizures, developmental delay, and striking craniofacial/dental abnormalities, including hypomineralized enamel, occlusal wear, and early loss of primary teeth. While TBCK plays a role in vesicle transport and may interface with PI3K- AKT-mTOR signaling, its precise cellular function remains unknown. Understanding how TBCK regulates intracellular pathways and tissue-specific outcomes is critical to identifying actionable mechanisms of disease. I propose to use the developing tooth enamel as a high-resolution model to study TBCK-regulated vesicle transport and matrix mineralization. Ameloblasts are the epithelial cells responsible for producing tooth enamel, and they rely on vesicle-mediated transport to control mineralization. In preliminary work, I found that TBCK is highly expressed in maturation-stage ameloblasts localizing to the apical pole, where it appears to regulate vesicle transport. TBCK knockout (Tbck-/-) mice recapitulate dental features in children and show disrupted enamel mineralization, altered endosomal markers, and mTOR signaling abnormalities. Therefore, I will test the central hypothesis that TBCK activates AKT to stimulate mTOR signaling and promote vesicle transport in ameloblasts; and in TBCK's absence, lysosome transport failure results in protein matrix retention and weak, under-mineralized enamel. Aim 1 will determine whether TBCK regulates mTOR-mediated vesicle transport in ameloblasts. Using single- cell RNA sequencing, spatial transcriptomics, my validated in vivo vesicle transport assay, and pharmacologic modulation of the mTOR pathway, I will define how TBCK affects endo-lysosomal dynamics in ameloblasts. Aim 2 will define the structural and physiochemical effects of TBCK loss on developing enamel. I will apply a multimodal pipeline to map the disturbances in developing enamel missing TBCK. We propose to use innovative methods for mineralized tissues, such as focused-ion beam/scanning electron microscopy (FIB/SEM) coupled with energy dispersive spectroscopy (EDS), Raman Spectroscopy, and nanoindentation to map mineral density, ionic content, and mechanical strength of the enamel matrix in Tbck-/- mice across developmental stages. Aim 3 will assess whether exfoliated primary teeth from children with TBCK syndrome reflect the enamel defects seen in the mouse model. I partnered with the TBCK Foundation to collect patient teeth and correlate enamel composition and structure with clinical neurodevelopmental metrics from the TBCK Natural History Study. This work will establish enamel as a model for studying intracellular signaling and mineralization, while also laying the foundation for using primary teeth as retrospective indicators of systemic disease. By bridging developmental biology with patient-centered diagnostics, this project provides an innovative platform for understanding rare pediatric syndromes and discovering new avenues for early intervention.


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 = $162,508 )
2026	2026	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Oral Diseases and Disorders Research	000	1	7/8/2026	NEW	$162,508
														Subtotal = $162,508

Grand Total All Awards = $162,508

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Mapping the developmental effects of TBCK loss in dental and craniofacial mineralization

Award Number: K08DE035951

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/06/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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