UH3DE028872

Enamel Atlas: Systems-Level Amelogenesis Tools at Multiple Scales - Abstract

Enamel defects, whether congenital, acquired, or environmental in origin, are associated with a significant cost to society and also 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. We have identified at least two factors that have delayed progress, and which we propose to address in this application.

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 take into account. 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 propose to take full advantage of these recent technical advances and of the complementary expertise of our team to create an integrated, multi-modal set of tools and reference materials. Specifically, we will generate innovative mouse reagents, including amelogenesis-stage specific CRE drivers, reporters, and conditional knockout and knock-in models of key structural and proteolytic players that constitute the enamel matrix. This will enable a workflow to profile 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 the 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.

San Francisco Regents Of The University Of California

NOT APPLICABLE

93.121 - Oral Diseases and Disorders Research

National Institute of Dental and Craniofacial Research (NIDCR) [HHS - NIH]

California United States

State-Wide

Encouraging Development of Novel Amelogenesis Models (UG3/UH3 Clinical Trial Not Allowed) (RFA-DE-19-004)

Amendment Since initial award the total obligations have increased 201% from $644,123 to $1,937,228.