Recent advances in developmental biology, computational and genome science, and tissue engineeringhave made it possible to contemplate the regeneration of mammalian organs. The integration of knowledgefrom these disparate fields now enables the study of how individual components combine on a global scaleto generate particular biological structures and functions. The application of such a systems-basedapproach to the problem of tooth engineering will make it possible to pursue rational rather than empiricstrategies to fabricate a properly differentiated, enamel bearing tooth in vitro. Owing to current knowledge ofthe genetic pathways involved in odontogenesis and its clinical accessibility, the tooth represents an idealtarget organ for the SysCODE Consortium. Like many mammalian organs, the tooth forms via a commondevelopmental mechanism that involves the sequential, ordered exchange of signals between interactingepithelial and mesenchymal cell populations. We hypothesize that this complex, dynamic regulatorynetwork can be resolved at the genetic and ultimately molecular level by the integration of different scientificdisciplines and that this information can be used in the form of a molecular blueprint to design and build atooth. To accomplish this goal, we propose three Specific Aims.
In Aim 1, we will generate a dynamic timeseries of spatially resolved gene expression lists for the interacting epithelial and the mesenchymal cellpopulations that regulate early tooth morphogenesis. These analyses will be expanded to include selectmouse mutants, limited proteomic data for abundant ECM proteins (w/ Project 5), and micromechanicaldesign principles (w/ Project 6).
In Aim 2, in conjunction with the SysCODE Computational Team, we willsynthesize this information into a gene regulatory network (GRN), and with other data, into a molecularblueprint for early tooth development. This will involve the identification and ordering of canonical signalingpathways between dental epithelium and mesenchyme and analysis of transcriptional regulatory networksusing new genomic and computational tools. Lastly, in Aim 3, we will employ tissue engineering platformsdeveloped in Projects 7 and 9 in conjunction with the molecular blueprint and engineering design principlesto direct tooth development in vitro. In sum, this Project has the potential to provide a paradigm for howinterdisciplinary research can address a high impact problem whose solution can transform medicine.
|Zhang, Jin; Ratanasirintrawoot, Sutheera; Chandrasekaran, Sriram et al. (2016) LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency. Cell Stem Cell 19:66-80|
|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|
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