Funding opportunities

The roles of non-coding RNAs in the self-renewal and differentiation of pluripotent stem cells

Funding Type: 
New Faculty II
Grant Number: 
Principle Investigator: 
Funds requested: 
$1 499 994
Funding Recommendations: 
Grant approved: 
Public Abstract: 
Statement of Benefit to California: 
Review Summary: 
This proposal is focused on defining the possible roles of non-coding (nc) RNAs, such as microRNAs (miRNAs), in controlling self-renewal and pluripotency of embryonic stem cells (ESC) and induced pluripotent stem (iPS) cells. The principal investigator (PI) proposes to functionally validate pluripotent cell-specific miRNAs by modulating their expression in mouse and human cells (aim 1), and to screen for miRNAs that rescue the differentiation defects of mouse ESC that lack the miRNA biogenesis machinery (aim 2). Lastly, the applicant proposes to identify novel ncRNAs that regulate self-renewal, and specifically focus on identifying RNAs associated with a RNA binding protein known to promote pluripotency (aim 3). This is an innovative, clearly presented proposal that will identify the role miRNAs play in both ESC and iPS cells. It is based on strong evidence in the field that the miRNA machinery can influence stem cell properties. The proposal addresses an exciting research area, and pursues important tool development. Aims 1 and 2 are solid; reviewers lauded the overall experimental design, but pointed out that the proposed readout for assessing self-renewal/pluripotency may need improvements. Furthermore, the proposal would benefit from expanding the number of human embryonic stem cell (hESC) lines under investigation to allow evaluation of the reproducibility of identified responses to changes in miRNA expression. Finally, reviewers expressed concern that potential variability in the proposed screen, due to varying expression levels within the miRNA overexpression library, and the heterogeneity of ESC cultures, was not sufficiently addressed in the discussion of potential pitfalls. A reviewer questioned the feasibility of aim 3, as it depends on the availability of certain reagents that have not yet been developed. Notwithstanding these specific suggestions and criticisms, reviewers were overall very enthusiastic about the innovation and research design presented in this proposal and about its potential for facilitating progress toward therapeutic approaches using hESC and/or iPS cells. Since preliminary data were considered relatively weak, the proposal was judged to be high risk but potentially highly rewarding. The reviewers expressed confidence that important insights will be gained from the proposed work. The principal investigator (PI) has only recently been appointed as an assistant professor, and has already attracted some extramural funding. She/he is an exceptional scientist with an outstanding record of publication in the miRNA field, including a number of publications in very high profile journals. She/he was trained by one of the world leaders in the field of miRNA biology, and obtained the expertise necessary to create mouse knockouts as a graduate student. miRNA research is extremely competitive, but the PI appears to be very well trained to be successful in this field of research. The PI has only a limited stem cell background, which is partly addressed by establishing collaborations, and by the fact that the home institution has a strong stem cell center, and a strong commitment to the development of the stem cell biology program. The mentoring plan is solid. Given his/her overall track record it is highly likely the PI will be a future leader in the field. A strong letter of support from the head of the PI’s division was included. The PI has very little administrative or teaching duties, which will allow him/her to focus on research. A generous start-up package with a full laboratory suite and support for graduate students was provided. Extensive core facilities are readily accessible.

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