Funding opportunities

Mechanisms of neural stem cell self-renewal and differentiation in the brain and cancer

Funding Type: 
New Faculty II
Grant Number: 
RN2-00937
Funds requested: 
$2 207 340
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Neural stem cells are a group of cells that can reproduce themselves (self-renewal) and become other specialized neural cells such as neurons (differentiation). These two abilities of neural stem cells present the hope for replacing lost or damaged neural functions caused by disease or injury. In addition, genetic mutations in neural stem cells may be the cause of brain cancers. Therefore, one exciting outcome of neural stem cell study is the potential of finding treatments both for neurodegenerative diseases and nerve injury, as well as for brain cancers. Two general strategies of neural stem cell therapy are being actively explored. One approach is to harness the potential of the existing neural stem cells in the brain to repair functional deficit. Another approach is to introduce neural stem cells cultured outside the body to replace lost or damaged function. For both approaches to work as we hope, we must learn more about how neural stem cells can be maintained in the stem cell state and how they can be guided to become a correct type of neurons to fulfill the specific function. A better knowledge of neural stem cell biology will help guide us to fully utilize the potential of neural stem cells (recovery of functions) but reduce the associated risk (tumor formation) in developing novel therapy. The goal of our research is to better understand the biology of neural stem cells for the purpose of more effective use of their regenerative power. We have recently identified two cell signaling molecules, ephrin-B and Galpha, as critical players in regulating neural stem cell self-renewal and differentiation in the mouse brain. Specifically we have found that ephrin-B signaling is important for maintaining neural stem cells in the stem cell state, while Galpha signaling is important for promoting neural stem cells to become neurons. We propose to start from these two molecules to further identify the mechanisms controlling both normal and cancerous neural stem cells. A better knowledge of the mechanisms will provide more opportunities for developing stem cell therapeutics.
Statement of Benefit to California: 
Neurodegenerative diseases and brain cancers affect tens of thousands of people in California, but there are no available cues or effective treatments. Neural stem cells carry the promise of providing treatments for neurodegenerative disease such as Parkinson's and Alzheimer's diseases, and they may also hold the key for understanding the cause of brain cancers. Our proposed study will bring benefit to people in California in several ways. First, our study on normal neural stem cells will yield important knowledge on how they are regulated by intrinsic and environmental factors. This knowledge will be useful for developing effective stem cell replacement therapy by providing insight on how to maintain and grow neural stem cells in culture and how to guide them to generate correct neuron types for a particular neurodegenerative disease. Second, our study on cancerous neural stem cells will lead to identification of novel drug targets and development of future treatments for brain cancers. Finally, a better knowledge of both normal and cancerous neural stem cells will be instrumental for developing a safe neural stem cell based replacement therapy.
Review Summary: 
This investigator proposes to study the role of Ephrin B and G protein alpha (G alpha), two specific signaling cascade molecules that oppose each other to control the balance between stem cell maintenance and differentiation. The first specific aim is to explore the mechanisms of G alpha signaling in mouse neural stem cells: the applicant will study cortical phenotypes in mice that lack or express very high levels of G alpha signaling molecules throughout development. The second specific aim is to determine if G alpha signaling plays a role in neural stem cells of the sub ventricular zone and dentate gyrus of adult animals. Changes in expression levels of this signaling molecule will be achieved both using genetic models (knock-outs, knock-ins and conditional models) and by electroporation of inhibitory RNAs. In the third specific aim, the applicant will examine the expression and function of Ephrin B in human brain cancer stem cells. Overall, reviewers commented that this was a proposal from a hard-working applicant who has published relatively well as a trainee. However, the applicant presents a poorly focused and overly ambitious research plan that is not especially creative, and contains a poor description of outcomes and data interpretation. The principal investigator (PI) has a number of useful tools and reagents including gain-of-function and loss-of-function assays. Reviewers commented that the main strengths of this proposal are the availability of the mutant mice, the applicant’s familiarity with mouse genetics, and a logical albeit ambitious backup plan. However, the applicant only poorly elaborates on the biological insight to be gained from setting up these extensive and expensive experiments. The proposed analysis of the genetically complex animals is very superficial, barely exceeds a few lines in each aim, and is very generic. Thus, reviewers felt that the applicant will not be able to gain significant knowledge from the experimental plan described. They agreed that the weakest part of the application is the final aim of studying Ephrin B as a potential stem cell marker in gliomas. It is clear that the PI does not have ready access to patient tissue, the proposed back-up plan of using cell lines is inadequate, and the science invoked to support the PI’s hypothesis is superficial and not supported by the literature or by the preliminary data. The applicant was described as having a strong record as a student and postdoctoral fellow. The publication record since becoming independent is poor, but some articles are forthcoming. These articles contain key preliminary data to support this present grant application. The mentoring plan proposed is adequate but not strong. Reviewers commented that there is adequate institutional support and clear evidence that the institution tries to invest in stem cell research. The institutional letter of support seemed very supportive of the applicant. In summary, reviewers felt that this was a weak proposal from a moderately promising candidate.
Conflicts: 

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