Basic Biology III
The role of metabolism in stem cell biology is poorly understood. Studies have shown that changes in metabolism coincide with differentiation of stem cells into adult tissue cells. However, what regulates these metabolic changes and whether they are important for differentiation is yet unknown. This proposed research will better characterize the metabolic changes that occur during human embryonic stem cell differentiation. It will also investigate what regulates these metabolic changes in stem cells. Importantly, this study will determine the role of these metabolic changes in stem cell self-renewal, pluripotency, and differentiation. Findings from this research will improve our understanding of the role of metabolism in stem cell biology and may lead to novel approaches for regenerative medicine involving metabolic programming or reprogramming of stem cell fate.
Statement of Benefit to California:
Our research will have short- and long-term benefits for the citizens of California. In the short-term, our research will explain critical unanswered questions about stem cell differentiation. Specifically we will elucidate the role of metabolism in stem cell biology and differentiation. This proposed research may uncover strategies for controlling differentiation of stem cells by manipulating their metabolism. Future research will build on this to metabolically program stem cells into adult tissue cells or reprogram adult tissue cells into pluripotent cells useful for regenerative medicine. In the long term, our research into the role of metabolism in stem cells may help clinicians stop the spread of teratomas, thus making stem cell-based therapies safer. This development could benefit millions of Californians afflicted with diseases such as neurological disorders and diabetes.
Project Synopsis: The goal of the research proposed in this application is to investigate mechanisms that control changes in energy metabolism that occur in human embryonic stem cells (hESCs) as they undergo differentiation. The study is based on the observation that proliferating hESCs rely primarily on glycolysis and then switch to mitochondrial oxidative metabolism upon differentiation. The first specific aim is to rigorously characterize hESC metabolism during differentiation. The second aim is to alter energy metabolism in hESCs and examine the effects on self-renewal, pluripotency, and lineage differentiation in vitro. Significance and Innovation: - The proposal addresses an important area of research - stem cell metabolism - and could provide new insights into mechanisms of pluripotency and differentiation. - The study is not particularly innovative, as previous investigations have characterized changes in mitochondrial metabolism upon differentiation of hESCs. - The proposed research would likely have only a modest impact. Feasibility and Experimental Design: - The research plan is substantially lacking in essential experimental details and is primarily a list of methods to be employed. - A major weakness of the proposal is the lack of adequate preliminary data supporting the experimental rationale. - A key strength of the study is its focus on the role of glycolytic metabolism in maintaining pluripotency and promoting hESC self-renewal. - Reviewers were unclear how the proposed experiments would lead to the definitive identification of the relevant metabolic regulators and felt that the study lacked adequate mechanistic focus. Principal Investigator (PI) and Research Team: - PI is well trained, with significant experience studying glycolysis and metabolism as a postdoctoral fellow. - The team did not have adequate stem cell expertise; the PI has no experience with stem cells, and a collaborator possessing such expertise will commit only 1% effort. - The PI has yet to publish or demonstrate productivity as an independent investigator. - The reviewers suggested that this talented young investigator seek out ways to improve his/her grantsmanship skills. Responsiveness to the RFA - Reviewers considered the proposal to be largely responsive in that it focuses on cellular processes critical for the regulation of hESC fate and renewal.