Funding opportunities

Control of pluripotency and reprogramming by a unique PolIII complex

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06200
Funds requested: 
$1 353 349
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Pluripotent stem cells have enormous potential for developing new treatments for a myriad of human diseases and disorders. In addition they provide a unique window into the development of our own species. In order for these stem cells to reach their full potential we must have a much better understanding of how they grow and how they can be turned into specialized cells that could be used to treat patients. The present proposal describes studies designed to study a new factor that seems to be important for the growth of stem cells. This factor is part of a complex of proteins whose function in stem cell biology had not been appreciated. Understanding how this protein complex works in stem cells could aid in our development of new cell-based therapies and give new insights into the mechanisms that normally control human development. In addition understanding how these proteins work could aid in the development of new stem cell lines from patients which could then be used to study disease processes.
Statement of Benefit to California: 
A goal of Prop 71 is to turn stem cell research to clinical application. Disability and loss of earning resulting from a disease or disorder are devastating and are a financial burden for California in addition to patient suffering. Therapies using human ES cells and induced pluripotent stem cells (hiPSCs) could change lives. Using these cells as models of disease will help us understand underlying causes and aid drug development. For this potential to be realized, we need a better understanding of how stem cells grow and what regulates their self-renewal. Maintenance of stem cells in an undifferentiated state is problematical and long term growth of stem cells can be associated with genetic alterations, some associated with cancer. Understanding mechanisms regulating stem cell growth will be important in maintaining stem cells, understanding both how to differentiate them to specialized cells and the risks of transplanting cells into patients. The proposed research should provide fundamentally better understanding of how hESCs and hiPSCs grow and self-renew. Anticipated benefits of our research to Citizens of California include: 1. Development of improved methods for growing stem cells and developing cell-based treatments 2. Understanding risks of transplantation 4. Improved understanding of early embryo development 6. Revenues from technology and intellectual property 7. Creation of new biotech companies 8.Creation of new jobs in the biotech sector.
Review Summary: 
The applicant proposes to investigate the role of a subunit of the RNA polymerase III (Pol III) complex in stem cell growth and pluripotency. Pol III is an enzyme that synthesizes small RNAs required for the proliferation and function of all eukaryotic cells. The proposed experiments are focused on assessing the subunit’s role as a key regulator of human embryonic stem cell (hESC) and human induced pluripotent stem cell (hiPSC) identity and pluripotency. In specific aim 1, the applicant proposes to determine the global association of the Pol III subunit with chromatin in human pluripotent stem cells (hPSCs). The second aim is focused on evaluating the effect of the Pol III subunit on expression of messenger RNA and microRNA in hPSCs. The third aim will determine the effect of the subunit on cellular reprogramming and the stability of the pluripotent state. Significance and Innovation - Reviewers questioned the significance of this study, since the Pol III subunit under investigation is one of hundreds of components downstream from the key pluripotency factors, and the rationale for studying this particular component was unconvincing. - Reviewers were not convinced that the project would have a major impact or advance the field significantly. - The focus on the Pol III subunit was recognized as novel, as previous studies have not investigated the role of this component in pluripotency. Feasibility and Experimental Design - Reviewers expressed some concerns about the specificity of antibodies used for chromatin binding analyses and questioned other details of some proposed experiments. -While a significant amount of high quality preliminary data supports the proposed study, it is not clear whether this RNA Pol III complex plays an important role in many cells or if it is unique to stem cells. - The experimental design is generally sound, and experimental aims are achievable. Principal Investigator (PI) and Research Team - The PI is an excellent stem cell scientist with appropriate expertise and necessary qualifications to carry out the proposed study. - Reviewers expressed some concerns about the PI’s recent productivity. - The proposed research team was recognized as solid, well qualified and appropriate. Responsiveness to the RFA - The proposed investigation is completely responsive to the RFA.
Conflicts: 
  • William Matsui

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