Recent advances in developmental biology, computational and genome science, and tissue engineering have made it possible to contemplate the regeneration of mammalian organs. The integration of knowledge from these disparate fields now enables the study of how individual components combine on a global scale to generate particular biological structures and functions. The application of such a systems-based approach to the problem of tooth engineering will make it possible to pursue rational rather than empiric strategies to fabricate a properly differentiated, enamel bearing tooth in vitro. Owing to current knowledge of the genetic pathways involved in odontogenesis and its clinical accessibility, the tooth represents an ideal target organ for the SysCODE Consortium. Like many mammalian organs, the tooth forms via a common developmental mechanism that involves the sequential, ordered exchange of signals between interacting epithelial and mesenchymal cell populations. We hypothesize that this complex, dynamic regulatory network can be resolved at the genetic and ultimately molecular level by the integration of different scientific disciplines and that this information can be used in the form of a molecular blueprint to design and build a tooth. To accomplish this goal, we propose three Specific Aims.
In Aim 1, we will generate a dynamic time series of spatially resolved gene expression lists for the interacting epithelial and the mesenchymal cell populations that regulate early tooth morphogenesis. These analyses will be expanded to include select mouse mutants, limited proteomic data for abundant ECM proteins (w/ Project 5), and micromechanical design principles (w/ Project 6).
In Aim 2, in conjunction with the SysCODE Computational Team, we will synthesize this information into a gene regulatory network (GRN), and with other data, into a molecular blueprint for early tooth development. This will involve the identification and ordering of canonical signaling pathways between dental epithelium and mesenchyme and analysis of transcriptional regulatory networks using new genomic and computational tools. Lastly, in Aim 3, we will employ tissue engineering platforms developed in Projects 7 and 9 in conjunction with the molecular blueprint and engineering design principles to direct tooth development in vitro. In sum, this Project has the potential to provide a paradigm for how interdisciplinary research can address a high impact problem whose solution can transform medicine.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Linked Research project Grant (RL1)
Project #
Application #
Study Section
Special Emphasis Panel (ZRR1-SRC (99))
Program Officer
Lumelsky, Nadya L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Arbab, Mandana; Sherwood, Richard I (2016) Self-Cloning CRISPR. Curr Protoc Stem Cell Biol 38:5B.5.1-5B.5.16
Hashimoto, Tatsunori; Sherwood, Richard I; Kang, Daniel D et al. (2016) A synergistic DNA logic predicts genome-wide chromatin accessibility. Genome Res 26:1430-1440
Barkal, Amira A; Srinivasan, Sharanya; Hashimoto, Tatsunori et al. (2016) Cas9 Functionally Opens Chromatin. PLoS One 11:e0152683
Arbab, Mandana; Srinivasan, Sharanya; Hashimoto, Tatsunori et al. (2015) Cloning-free CRISPR. Stem Cell Reports 5:908-917
Lu, Yu; Loh, Yuin-Han; Li, Hu et al. (2014) Alternative splicing of MBD2 supports self-renewal in human pluripotent stem cells. Cell Stem Cell 15:92-101
Brock, Amy; Krause, Silva; Li, Hu et al. (2014) Silencing HoxA1 by intraductal injection of siRNA lipidoid nanoparticles prevents mammary tumor progression in mice. Sci Transl Med 6:217ra2
Sherwood, Richard I; Hashimoto, Tatsunori; O'Donnell, Charles W et al. (2014) Discovery of directional and nondirectional pioneer transcription factors by modeling DNase profile magnitude and shape. Nat Biotechnol 32:171-178
Tasoglu, Savas; Safaee, Hooman; Zhang, Xiaohui et al. (2013) Exhaustion of racing sperm in nature-mimicking microfluidic channels during sorting. Small 9:3374-84
Arbab, Mandana; Mahony, Shaun; Cho, Hyunjii et al. (2013) A multi-parametric flow cytometric assay to analyze DNA-protein interactions. Nucleic Acids Res 41:e38
Nusinow, David P; Kiezun, Adam; O'Connell, Daniel J et al. (2012) Network-based inference from complex proteomic mixtures using SNIPE. Bioinformatics 28:3115-22

Showing the most recent 10 out of 23 publications