Funding opportunities

Laying the groundwork for building a tooth: analysis of dental epithelial stem cells

Funding Type: 
New Faculty II
Grant Number: 
RN2-00933
Principle Investigator: 
Funds requested: 
$3 075 251
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Statement of Benefit to California: 
Review Summary: 
The applicant focuses on teeth as a model for understanding regenerative processes of complex organs. Despite their accessibility and recent published work demonstrating the clinical feasibility of tooth regeneration, little is known about the genetic regulation and biology of the cells that participate in tooth regeneration. This application is directed at filling in some of the gaps in this knowledge. The applicant uses mouse incisors as a source of continually growing epithelial progenitor cells and proposes to establish the incisor as a model for dental stem cell biology. The applicant also proposed studies to isolate tooth epithelial stem cells from human embryonic stem cells (hESC). The applicant proposes a plan for identification of the epithelial stem cells and their mechanisms of self-renewal. Then the applicant will establish the optimal conditions for growing epithelial (progenitor) cells from incisors and for maintaining their undifferentiated state. The applicant will examine the potential of these epithelial cells and mesenchymal stem cells (or the two in combination) in tooth regeneration. This area of stem cell biology was considered an important area for CIRM to emphasize as it is currently underdeveloped and inadequately supported. Reviewers felt that the novelty of the proposed work was high, and that the proposal was quite high risk, but also had great potential to be high gain. The reviewers noted that though published work supporting Aim 1 was extant, the applicant is significantly extending the work by examination of cell adhesion molecules and assessing the role of particular growth factors in the biology of this stem cell population. Overall, the proposed studies would not have been thought feasible in the hands of most young investigators, but because of the particular strengths of this new investigator and the enormous institutional support, reviewers were very confident that both basic science insights into epithelial stem cell biology and practical, clinically relevant information would emerge from these studies. Reviewers expressed some concern that the over-arching hypothesis was not presented clearly. Another cited weakness of the application was the lack of adequate characterization of the cells, but extant literature should help guide the characterization of these epithelial stem cells in vitro. Reviewers felt that, in the regeneration studies, the applicant did not sufficiently account for the niche or microenvironmental effects, and the culture system was simplistically discussed. The microenvironment may have to be considered in greater detail in order for the generation of epithelium from hESC to be successful. These considerations led reviewers to conclude that the tooth regeneration studies were risky in terms of feasibility. Much of the proposed work for Aim 1 appears to have been published, likely a problem with the timing of submission of this application and the paper. Some criticisms that the application was too large in scope and speculative were raised, but again, these concerns were balanced by a highly favorable impression that the applicant has already tackled difficult problems successfully. The greatest strength of the grant is the Principal Investigator. Although she/he has been an assistant professor of orofacial science and pediatrics at a prestigious medical center only since 2007, she/he is already a widely recognized scientist with highly significant publications, including some as senior author. The applicant communicated great motivation and clear determination to accomplish the research. Though there were some problems with the proposed science in the grant, the applicant is likely to overcome these given the applicant’s and institutional strengths. Reviewers felt that the potential for this applicant to be a leader in the field was high. The institutional support for this applicant could not have been more positive. The extraordinary level of institutional support was clear in a letter signed by the dean, chair, division director and the director of the institutional stem cell center. Importantly, the applicant will have a 90% protected research time allotment, another indication of the institution’s commitment to the applicant’s project.
Conflicts: 

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