Funding opportunities

Exploring the role of WNT signaling in neural progenitor cells

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-05883
Funds requested: 
$1 371 330
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Human pluripotent stem cells (hPSCs) and their derivatives represent the only research tool to study human development. As such, these cells allow us to study the progression of diseases at the cellular level in a dish, probe how specific genetic defects contribute to the myriad of developmental and birth defects, and generate the “raw material” for the development of cell-based therapies of presently incurable diseases, such as cancer, cardiovascular disease, and neurodegenerative disorders. However, our understanding of the basic mechanisms underlying stem cell biology is incomplete, and the processes by which individual cells organize each other to give rise to the complexity of multi-cellular life remain mysterious. At the heart of embryonic development, and hence stem cell biology, lies an intricate process of cell communication. Individual cells produce and release signals, known as growth factors, that instruct neighboring cells to assume specific behaviors and properties. WNT proteins represent a major class of growth factors with potent effects on stem cells and developmental processes. We will examine the role of these WNT proteins in neural stem cells, a cell type that can generate many of the cells found in the central nervous system. Identifying the mechanisms by which WNT proteins act will contribute valuable tools and protocols for the manipulation of hPSC and neural stem cells into mature cell types suitable for cell replacement therapies and disease modeling.
Statement of Benefit to California: 
The rise in life expectancy to over 80 years will likely lead to an increase in the number of people suffering from age-related diseases, such as cancer and neurodegenerative disorders. Current medical treatments do not cure such diseases. Recent advances in the study of human pluripotent stem cells (hPSCs) have provided the opportunity to develop novel cell replacement therapies for the treatment of many such diseases. Development of novel cell-based therapies will also overcome the inadequacy of conventional drug-based treatments. A major challenge in the study and use hPSCs is to develop robust methods for the directed differentiation of hPSC into functionally mature cell types suitable for therapeutic applications. Our research seeks to gain a better understanding of how to manipulate neural stem cells, a population of cells capable of differentiating into neurons. The proposed research is fundamental to applications of hPSC in regenerative medicine and has broad benefits to researchers with a wide spectrum of scientific interests. The outcome of this project will benefit medical research and provide great benefits to the advancement of California biotechnology. The patents, royalties and licensing fees resulting from the proposed research will provide tax revenues. The proposed research provides not only the foundation for the scientific advances in regenerative medicine to improve health, but also technology advancement and financial profit for the people of California.
Review Summary: 
WNT proteins represent a major class of growth factors with potent effects on stem cells and developmental processes. The applicants propose to examine the role of WNT proteins in neural stem cells and identify the mechanisms by which WNT proteins act on human pluripotent stem cell (hPSC) and neural stem cell differentiation. They propose to dissect the role of each individual WNT protein in iPSC derived NPC from patients harboring mutations in a gene that disrupts the function of WNT proteins. Recombinant WNT proteins then will be added to these cells to determine how each WNT regulates self-renewal and differentiation in NPCs. Significance and Innovation -Although this project may provide novel insights into the basic mechanisms by which WNT signaling regulates stem cells, some reviewers were not convinced that it would lead to a real breakthrough. They noted that WNT has likely very complex effects on neuronal development that will be difficult to tease apart with the proposed assays. - This project uses an innovative approach to study WNT signaling in iPSC line and may inform possible use of WNT in culture conditions for these cells. Feasibility and Experimental Design - It is not fully clear why they propose 4 independent approaches to target the gene that is important for WNT protein function and why all those routes need to be performed in parallel. -It was previously suggested that canonical WNT signaling maintains progenitors whereas non-canonical WNT signaling favors differentiation, thus it is not clear what is the novelty in experiments described in Aim 2 and Aim 3. Aim 3 is not integrated with the rest of the research plan. Principle Investigator and Research Team -While the PI has expertise in neuronal stem cells and WNT signaling, his track record of publications is modest -The co-investigator provides the appropriate expertise but the overall personnel budget seems excessive. Responsiveness to RFA -The proposed research addresses the stated objectives of the RFA, including the cellular and molecular characterization of human stem and progenitor cell populations and understanding basic molecular mechanisms of stem cell biology
Conflicts: 
  • Ali Brivanlou

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