Funding opportunities

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: 
Human embryonic stem cells (hESC) are being considered for a wide range of research and therapeutic uses. Cell therapy is the most challenging of the potential clinical applications and its success will depend on the ability to guide differentiation of hESC into clinically useful cell types. The ideal cell types would possess three features: the capacity to restore lost functions, the ability to survive after transplantation, and the absence of malignant potential. A major roadblock in the development of stem cell therapies is the lack of tools for quality control, characterization, and identification of human pluripotent stem cells and differentiated populations. As new cell lines are developed and new differentiation techniques are tested, the need for validation of the cells becomes more and more critical if the cells are to be used in a clinical setting. We have developed a new method for unequivocally identifying pluripotent stem cell populations using molecular analysis tools developed for the Human Genome Project. We have identified a molecular fingerprint that is shared by all pluripotent cells, human or mouse, embryo-derived or produced from adult cells through new induced pluripotence technologies. Using the more than 10 million pieces of data we generated by analyzing hundreds of cell lines, we created a database called the The Stem Cell Matrix, which is intended to fill a critical knowledge gap in the field of human pluripotent cell biology. By collaborating with a company that has developed a powerful new search engine, we will be able to search these data for clues that will tell us whether a specific cell line is pluripotent, identify chemicals that may improve methods for reprogramming, and eventually link data from clinical trials with data on the genes that are active in the cells before they are transplanted. Our overall goal is to build on our proven technology to grow the database, providing a service that all CIRM-funded investigators can use for quality control and identification of the cells they are developing for research and clinical applications. An advantage of our approach is that the search engine can link our information to a much larger database on cancer cells, which will make it possible for stem cell researchers to develop new insights by comparing stem cells and cancer cells.
Statement of Benefit to California: 
The State of California, like the rest of the nation, faces immense challenges to its health care system, with soaring medical costs and an aging population. Pluripotent stem cells hold the potential to revolutionize medicine and health care by providing new treatments for incurable conditions such as diabetes, Parkinson's disease, and spinal cord injuries. Stem cell therapies, however, are in an early stage, and research conducted over the next few years will be critical to development of therapies that are safe and effective. We have developed a new technology that harnesses the powerful tools developed for the Human Genome Project to ensure quality control and simplify characterization of human stem cells used for research and clinical therapy. The technology links smoothly with databases and search engines that are being developed by the high tech industry. We propose to further develop this technology and make it available and accessible to stem cell researchers and clinicians throughout California. Ultimately, this technology, the discoveries it will enable, and its synergies with the high tech industry will benefit California by attracting highly skilled jobs and tax revenues, and by making the State a leader in a field that is poised to be the economic engine of the future.
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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