Funding opportunities

Molecular Mechanisms of Trophoblast Stem Cell Specification and Self-Renewal

Funding Type: 
New Faculty II
Grant Number: 
Principle Investigator: 
Funds requested: 
$3 078 580
Funding Recommendations: 
Grant approved: 
Public Abstract: 
Statement of Benefit to California: 
Review Summary: 
The main cell type comprising the placenta is the trophoblast. This application is focused on elucidating mechanisms of self-renewal and differentiation of human trophoblast stem (TS) cells. The proposal is based on the hypothesis that there is a relationship between hypoxia (here defined as a gas environment with oxygen concentrations below that of air), the expression of p63 and the formation or expansion of placental cell types. Thus, in the first aim the applicant will test this idea and expose cells isolated from placenta to hypoxic conditions and modulate expression of p63. Then, in aim 2, it is proposed to derive TS cells from human embryonic stem cells (hESC). Again the applicant will utilize the idea that hypoxia and modulation of p63 expression can affect the efficiency of the derivation process. Finally, in aim 3, the applicant wishes to identify regulatory factors critical for trophoblast differentiation. This well written proposal presents a focused project with a straightforward conceptual framework. It targets an important, under-studied area of research that may not only provide therapeutically important approaches to placental defects that cause intrauterine growth retardation, but may also provide new resources for stem cell derivation. Derivation of TS-like cells under hypoxic conditions from placenta samples is feasible and likely to be successful. As with most primary tissues, lowering the oxygen tension has drastically positive effects on the ability of cells to expand in vitro. However, one reviewer questioned whether assumptions made about the oxygen tension in placental tissue are valid, and another doubted whether hypoxic conditions will specifically promote derivation of proliferating trophoblast cells. Furthermore, some reviewers questioned the assumption that hESC have the capacity to differentiate into TS cells. Even though a number of reports suggest that hESC rapidly differentiate into some extraembryonic lineages, the true nature of these cells is not known. One reviewer pointed out that the only way the field will definitively answer this question is to have scientists dedicated to placental biology working on the problem. A reviewer also questioned the significance of aim 3; even though the proposed microarray studies are doable, it is not clear how the work will contribute to what is already known. Notwithstanding these specific concerns, reviewers appreciated the large potential impact of this work, as this proposal targets the important, yet understudied health issues caused by placental defects. The applicant is an outstanding physician-scientist and an ideal candidate for a New Faculty Award. S/he started his/her independent position very recently, and has a good publication record, albeit little stem cell experience. The career development plan is well laid out and some of the milestones are very specifically stated. Since the investigator is working in an area with under-represented research effort, s/he is likely to become a leader in this area. The mentors include a preeminent placental scientist, although the nature of the mentoring relationship was not laid out in detail. The institutional commitment was judged to be excellent, including provision of ample space and equipment resources and adequate protection of time for research. The home institution is an excellent academic institution and is increasing its commitment to stem cell research.

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