Funding opportunities

Human Embryonic Stem Cells and Neural Crest Plasticity

Funding Type: 
SEED Grant
Grant Number: 
RS1-00334
Funds requested: 
$685 000
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Craniofacial anomalies and bone defects pose a difficult and challenging problem both for the doctor and for patients along with their families. A great demand exists for the repair of craniofacial bone defects. Orofacial defects repaired with grafts obtained from an orofacial donor site are usually more successful than those from non-orofacial sites. However, the efficacy is limited by high cost, donor morbidity, and scarcity of orofacial tissue sources. Some skeletal diseases such as cherubism, hyperparathyroid jaw tumor syndrome and craniofacial fibrous dysplasia affect only orofacial bones. Studies of the craniofacial skeleton also indicate that molecular mechanisms controlling skeletogenesis in the head are unique and distinctive from those occurring in other body sites. Neural crest cells are multipotent stem cells that contribute to a diverse array of tissues throughout the embryo. During craniofacial development, cranial neural crest contributes extensively to the formation of mesenchymal structures in the head and neck, such as orofacial bone, cartilage, tooth and cranial nerve ganglia. The majority of orofacial skeleton is neural crest derived. In this application, we propose to derive cranial neural crest-like progenitor cells from human embryonic stem cells and subsequently induce bone formation by these cranial neural crest-like cells. Bone tissues generated from cranial neural crest-like cells share similar developmental origin with craniofacial bones, thereby representing a superior therapeutic tissue source for craniofacial bone repair. The results from this proposal will be used to optimize strategies for maintenance of stem cell populations while improving our ability to stimulate the development of cell specific lineages needed for the repair and regeneration of defects in craniofacial tissues.
Statement of Benefit to California: 
Craniofacial anomalies and bone defects pose a difficult and challenging problem both for the doctor and for patients along with their families. A great demand exists for the repair of craniofacial bone defects. Orofacial defects repaired with grafts obtained from an orofacial donor site are usually more successful than those from non-orofacial sites. However, the efficacy is limited by high cost, donor morbidity, and scarcity of orofacial tissue sources. This proposal will benefit the people and the state of California by deriving cranial neural crest-like progenitor cells from human embryonic stem cells. Bone tissues generated from cranial neural crest-like cells share similar developmental origin with craniofacial bones, thereby representing a superior therapeutic tissue source for craniofacial bone repair.
Review Summary: 
This applicant proposes to isolate and characterize neural crest-like multipotent progenitor cells derived from hESC to determine the biological function of amelogenin in directing ES differentiation. He will then transplant these cells to evaluate their ability to repair and regenerate craniofacial tissues. SIGNIFICANCE AND INNOVATION: This application is somewhat innovative and original. Many investigators would like to find cells that could repair the organs or tisues that they are interested in. Dr. Zhou wants to do so with neural crest cells for craniofacial abnormalities. What is innovative is that Dr. Zhou already has a candidate molecule for differentiating the cells (amelogenin). The preliminary data suggests that alternatively spliced amelogenin will induce marker genes for osteogenesis, including the expression of frizzled/cadherin. Applying these cells to craniofacial abnormalities is of iinterest. STRENGTHS: • Dr. Yan Zhou is an experienced and productive investigator who has published 10 papers on various aspects of gene expression in tumors and other cells. He had obtained his PhD in 2000. • He has preliminary data indicating amelogenin will induce differentiation of cells. • He has excellent collaborators with whom he can work to apply these cells to craniofacial deformities. WEAKNESSES: This application appears somewhat schizophrenic. If the main goal is to derive craniofacial bone, then one would imagine that the authors should take a relatively unbiased approach to determining which factors in culture would best stimulate that process. In addition to things like dexamethasone, many candidate factors exist, including BMPs and Wnts. As a result, the focus on amelogenin seems out of place with the first aim as it is not clear from the background or preliminary data that amelogenin is necessarily a powerful bone-inducing factor. For example, there was no mention of whether amelogenin knockout mice have any craniofacial defects. Alternatively, if the main aim of the proposal is to understand amelogenin function, then a much more scientifically fruitful approach would be to focus on amelogenin knockout mice to better understand the physiological function of this protein. The current proposal tries to do a bit of both and as a result doesn't do a convincing job of either. Dr. Zhou seems to be a non-tenure track faculty member at USC, with no independent grant support. From the description of facilities it appears that he occupies space in somebody else's laboratory, perhaps Dr. Snead's. As a result, it is not clear how much institutional support there is for Dr. Zhou's work. Dr. Zhou has only published 4 first author or senior-author papers. DISCUSSION: Although the proposal fulfills many criteria for SEED grants, the exclusive focus on ameliogenin and the relatively weak record of the PI were seen as limiting factors.
Conflicts: 

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