Statement of Benefit to California:
SYNOPSIS: This proposal aims to identify small, organic drug-like molecules that can be used to promote the self-renewal or the directed differentiation of hES cells. This project will use chemical genetics and high-throughput screening to accomplish these two goals. Attention will be given to signal transduction pathways include Frizzled receptor, glia-derived neurotrophic factor receptor and Trk neurotrophin receptors. Organic synthesis will be used as well as chemical libraries. HSF-6, a USCF hESC line will be used. SIGNIFICANCE AND INNOVATION: Developing improved methods for the maintenance of pluripotency and self-renewal, as well as the directed differentiation of hES cells are important goals in stem cell biology. Hence identification of novel compounds that can support these fates is significant. The project is more innovative than many other applications that propose similar goals, as the PI is an expert in chemistry and chemical genetics. STRENGTHS: The strengths of this proposal include the chemical genetics approach with high-throughput screening, the PI's expertise, and the collaboration with others (Sato and Donovan). In total, this investigative team has a strong chemical genetics component with deep knowledge about small molecule screens, and includes well-established ES cell biologists. The PI is well-positioned to do these studies. WEAKNESSES: There were no overriding weaknesses in this proposal, although some preliminary data would have been helpful in assessing the feasibility of the effort. DISCUSSION: While the reviewers found no major weaknesses with the proposal, the lack of any genetic marker for neuronal differentiation in Aim 2 was mentioned.