New Faculty II
$3 029 897
Statement of Benefit to California:
The applicant proposes to study mechanisms of epigenetic control of early development. The premise is that an understanding of these mechanisms will guide manipulations of embryonic stem cells (ESCs) to allow ESCs to reach their full promise as developmental model systems and their full therapeutic potential. The specific focus of the research plan is on epigenetic regulation by classes of small non-coding RNAs distinguishable using transgenic mouse models which differentially affect the generation of these RNAs. In the first aim, the applicant will look at the complement of small non-coding RNAs during pre-implantation development by activating conditional knockouts of genes differentially affecting small RNA generation at different time points, then phenotypically characterizing these early embryos; isolating and analyzing certain small RNAs that may underlie interesting phenotypes; and finally, for promising small RNAs, looking for potential human homologs and performing subsequent expression analysis. In the second aim, the applicant will use wild type and the above-described transgenic mice to address the relationship of small non-coding RNAs to histone modifications. The reviewers uniformly noted that the proposed research is in an exciting and critically important area of basic research. Although there is no immediate or short-term therapeutic benefit, the proposed studies are likely to unravel mechanisms of development and provide a basis for manipulating ESCs to specific cell types, thus there is a high degree of significance for many disease applications. The reviewers found the proposal to be very well-written and considered the experimental plan to be a well-laid out. One reviewer found the research proposal to be ambitious, another commented that it was not overreaching in either the aims or the claims. All reviewers noted that the PI has already been working in the field and that this proposal is an extension of ongoing, funded work. The PI has demonstrated significant expertise in the techniques for each of the specific aims, and some preliminary data speaks to feasibility. The PI provided good detail in describing potential pitfalls and possible solutions. Several weaknesses in the proposal were discussed. Reviewers expressed concern over the difficulty of drawing conclusions relevant to normal embryonic development through the use of conditional knockouts. They noted that correlating the effects of such knockouts with precise points in development would be very difficult since the knockouts affect multiple components with varying kinetics. A reviewer did note that alternative methods for knockdown of the respective genes are likely to have similar problem in terms of kinetics and timing. Reviewers also noted the tremendous amount of work involved in isolating and analyzing, from thousands of murine embryos, the small RNAs that may underlie interesting phenotypes. Other concerns highlighted by the reviewers include the heterogeneity of the cell populations which could make it difficult to distinguish direct versus indirect effects of the small non-coding RNAs, and the lack of detail for applying findings from the mouse system to the human system. One reviewer noted that the only part of the proposal potentially not fundable by NIH is the transition to studies in hESC, and questioned the rationale for CIRM funding for this proposal. The PI has already demonstrated an ability to obtain NIH grants in exactly this area of research, and the proposed work is just an extension of his/her preliminary data. Despite these considerations, overall, the reviewers found the research plan to be very strong and interesting, albeit somewhat ambitious, and expected it to lead to interesting and interpretable results in this exciting and important area of stem cell research. The reviewers found the PI to be an exceptionally talented young investigator who has already made important contributions to the field of stem cells and is on a trajectory to have a stellar scientific career. S/he is a well-trained M.D./Ph.D. who completed a postdoctoral fellowship studying the epigenetics of development in an internationally known laboratory. S/he has been an independent investigator for about 3 years at the applicant institution and has significant extramural funding, including 3 grants from the NIH. The applicant has over 10 publications, including recent publications in high quality journals. The reviewers were mixed about the career development plan, one describing it as “modest” another as “very good”. It describes what the PI has already achieved and how s/he hopes to improve in three key areas: research, education, and leadership. A highly structured formalized mentoring plan is in place for the candidate, that includes mentorship from internationally recognized senior faculty, each of whom are experienced in mentoring and training. The institutional commitment to this spectacular young investigator is extraordinary in all aspects. There was a very strong letter of commitment from the institution, with significant financial support, along with an endowed chair for salary support. The PI has been given ample lab space, along with additional office areas and has access to considerable shared resources. The institution has a growing number of talented young scientists populating its stem cell program, and the environment is rich for collaboration. The institution has a very strong track record for developing leading scientists. In short, the institutional environment and commitment is superb. Overall, this is an exceptionally strong and well-written application from a talented young investigator working in a rich and nurturing environment.