Funding opportunities

Molecular mechanisms governing hESC and iPS cell self-renewal and pluripotency

Funding Type: 
New Faculty II
Grant Number: 
RN2-00922
Principle Investigator: 
Funds requested: 
$2 158 161
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Statement of Benefit to California: 
Review Summary: 
This application is focused on elucidating mechanisms that control self-renewal and pluripotency and might at the same time contribute to the tumorigenic potential of pluripotent stem cells. An emphasis is placed on the role played by the Myc gene in the regulation of embryonic stem cell self-renewal and during reprogramming using the Yamanaka procedure for generating induced pluripotent stem (iPS) cells. Although Myc is not necessary for the formation of iPS cells, it appears to enhance reprogramming significantly. In the first aim, the principal investigator (PI) will assess the function of Myc in mouse and human embryonic stem cells (hESC) by down-regulating its expression. In the second aim she/he proposes to identify Myc targets in hESC and also study association of these targets with particular epigenetic modifications. The third aim proposes a functional screen to identify novel enhancers and suppressors of reprogramming of adult somatic cells by screening either a hESC cDNA library or a short hairpin RNA (shRNA) library. Overall, this is a highly focused application, and the proposed studies have high significance for improving our understanding of basic stem cell biology and its clinical applicability. Reviewers expressed varying opinions regarding the proposed research plan but were uniformly enthusiastic about the applicant’s scientific leadership potential and the institutional commitment to him/her. One reviewer felt that given the broad interest in Myc as a reprogramming factor, studies related to Myc function are particularly timely, whereas another reviewer questioned the rationale for studying Myc in iPS cell formation when recent studies have suggested it is not required for that process. One reviewer expressed confidence that the intricate biological and molecular assays proposed should provide a substantial amount of data regarding the role of Myc in both self-renewal and pluripotency, whereas other reviewers pointed out that some of the proposed studies are not particularly innovative. One reviewer regarded the screens proposed in aim 3, although very ambitious, an interesting approach, whereas another reviewer questioned the feasibility of the screens based on experience in the field. Overall, feasibility of the project is supported by significant preliminary data both on the role of Myc in hESCs and the applicant’s ability to generate iPS cells using the Yamanaka method. The applicant is already an internationally recognized expert in Myc biology. She/he has been an independent investigator for two years, and his/her track record as reflected in publications, grant funding, honors and scholarship predict a highly promising career trajectory. The career development plan is fairly generic in scope and aims, but it does provide defined milestones in terms of publications and grants. The applicant put together a very strong mentoring committee composed of four senior researchers with widely divergent expertise, all of whom are at his/her institution. In addition, she/he has identified several other individuals who will serve as consultants or co-investigators and will contribute to mentoring activities. The environment for stem cell research at the home institution is exceptionally strong. Institutional commitment is presented in a fairly generic letter of support; research start-up funds and protected time for research are not specifically stated. Nevertheless, the institutional commitment to providing a rich collaborative environment through core facility access and numerous stem cell faculty is clearly evident. The applicant has been provided with a large amount of research space as well as dedicated cell culture and microscopy space. Overall, reviewers were very enthusiastic about this applicant and his/her potential to become a leader in the field. They considered the institution to be a major asset for the investigator as well. Although the research proposal could have been stronger, reviewers agreed that the proposed studies will advance our understanding and contribute substantially to stem cell biology.
Conflicts: 

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