EnamelBase: Objectives

Enamel defects, whether congenital, acquired, or environmental in origin, are associated with a significant cost to society and have profound psychological impacts. Despite significant progress over the last decade, the developmental process that gives rise to enamel, known as amelogenesis, remains poorly understood.

At least two factors have delayed progress.

• One is that existing mouse reagents, which provide the primary model for understanding genetic regulation of amelogenesis, have deficiencies that hinder dissecting the mechanisms in vivo.
• Another challenge is that new information regarding the nanostructure and phase composition of enamel have begun to emerge that prior models did not consider.

The ability to access powerful new genetic approaches, “omics” techniques and materials characterization methods therefore creates unprecedented opportunities to generate sophisticated new tools that will help push amelogenesis research to the next level.

We are working to create an integrated, multi-modal set of tools and reference materials. Specifically, we have generated a suite of innovative mouse models, including amelogenesis-stage specific constitutive and inducible Cre drivers, reporters, conditional knock-out, and targeted mutant models, that target structural and proteolytic proteins of the enamel matrix, trans-membrane ion transporters, and intracellular proteins associated with vesicular transport. For a comprehensive list, see the Mouse Models table.

Looking forward, these models will enable profiling transcription (using RNA sequencing) and translation (using proteomics) at specific developmental stages, and even on a single cell basis (using single-cell RNA sequencing).

Tissue and cell-level molecular profiling will be complemented by an in-depth characterization of the structure, composition, and mechanical properties of forming and mature enamel at overlapping length scales.

By mapping gene expression, specifying local proteomes, and quantitatively assessing impact of the perturbations at each of these levels on the materials properties of enamel, we will create a platform that will empower amelogenesis researchers, help delineate mechanisms of disease, and lay the groundwork to enable the development of new approaches of intervention.

Our overall approach is comprised of four distinct projects described here.