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The Stem Cell Matrix: a map of the molecular pathways that define pluripotent cells

Funding Type: 
Tools and Technologies I
Grant Number: 
RT1-01108
Principle Investigator: 
Funds requested: 
$1 141 124
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Statement of Benefit to California: 
Review Summary: 
The principal investigator (PI) proposes to continue an ongoing effort to characterize and classify human pluripotent stem cell lines and their derivatives. The PI previously led a research team to create a database that compiles data from hundreds of pluripotent cell lines and defines a molecular fingerprint of pluripotency. The PI proposes to add data from induced pluripotent lines, recently derived embryonic stem cell lines, and parthenogenic lines. In addition, the PI proposes to characterize and collect data from differentiating and differentiated cells. The goal is to refine and expand the database to allow for improved comparisons between embryonic stem cells, induced pluripotent stem cells, and differentiated cells. The database is publically accessible via the web and the PI will also generate a tutorial to facilitate mining of the database and linking it to chemical libraries and clinical trials. Reviewers recognized that the development of stem cell therapies requires sophisticated new tools for quality control, characterization and identification of human pluripotent stem cells and differentiated cell populations derived from them. They also noted that this research group has recently released a publicly accessible database of global gene expression profiles from pluripotent cell lines and their analysis has uncovered a protein-protein interaction network that is a shared feature of pluripotent cells. This global expression approach succeeded in identifying a gene expression signature for pluripotency whereas previous attempts by others using a different approach had demonstrated significant variability. The present proposal seeks to enhance the power and utility of this database and to develop a tutorial for users. Reviewers noted, however, that experimental validation of the identified molecular signature is necessary to know its importance and to understand if it is worth continuing the effort, but is not specifically proposed by the PI. Thus, a tutorial for the database could be premature. Nevertheless, reviewers felt the proposal would have broad impact and a high potential to advance our understanding of the genetic regulation of pluripotency. Reviewers agreed that the project was feasible and this has been demonstrated by the team’s development and recent publication of the gene expression database and the published comparison of the global profile of microRNAs in pluripotent and differentiated cells. The track record of the PI and established collaborations provide assurance that the aims will be completed. The PI and the research team have impressively strong and diverse expertise that is essential for the proposed project. The PI is a leader in the stem cell field. A reviewer expressed concern that the team is in transition as the two senior highly skilled members who are central to the proposal have embarked on clinical training, but plan to continue contributing to this work part-time. A PhD-level, bioinformatics specialist will also be recruited to the team. PROGRAMMATIC REVIEW A motion was made to move this application into Tier 1, Recommended for Funding. Reviewers were compelled to impart that this is an important database, which addresses a roadblock to stem cell research. Pluripotency (or stemness) is not that well defined, and to utilize information from approximately150 cell lines is not sufficient to achieve an adequate definition of pluripotency. The only way to reduce noise is to continue to increase the number of samples analyzed. Supporting this project will help us better understand the differences between iPS and embryonic stem cells and their utility for clinical applications. Reviewers again noted a weakness in the lack of data validation in the proposal but recognized that the scientific community can do such validation. A similar community validation has been successfully achieved with methylation analyses. Reviewers felt that the PI’s experience and established collaborations with shared resources contributed significant credibility to the success of this proposal. The motion to move this application into Tier 1 carried.
Conflicts: 

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