Human embryonic stem (hES) cells can serve as a biological repair system, with the potential to develop into many types of specialized cells present in the body. They can theoretically divide without limit to replenish other cells. When a stem cell divides, each daughter can remain a stem cell or adopt a more specialized role such as a muscle, blood or brain cell, depending on the presence or absence of biochemical signals. Thus, any therapeutic application will require the driving of the hES cells’ differentiation into particular specialized cells for transplantation into patients—for instance, beta cells to produce insulin for diabetics or dopamine-producing neurons to treat Parkinson’s disease. Controlling this differentiation process is one of the biggest challenges in stem cell research. Understanding of the mechanisms that regulate different differentiation processes helps to control the fate of hES cells in petri dishes to generate various cell types for regenerative therapy. Inside cells, proteins can be attached covalently to small proteins such as ubiquitin and SUMO under different biological conditions. It has been shown that ubiquitination and sumoylation play critical roles in regulating protein functions after they are linked to ubiquitin or SUMO. Many of the known targets of ubiquitination are the regulators for controlling cell growth, differentiation, proliferation and death. Sumoylation has been shown to be critical for gene transcription. It is reasonable to believe that these pathways will be involved in manipulating the fate of hES cells, affecting their behaviors under different chemical stimulus for differentiation. However, the molecular details of these processes are currently unknown. We propose to identify the cellular factors that are uniquely modified at different stages of hES cell development. The results obtained in this study will provide direct information about the regulatory process in hES cells at a proteome-wide level. This will lead to identification of important proteins that are specifically regulated in hES cell development, and help to design conditions and design therapeutic agents to manipulate ubiquitination or sumoylation pathway to control the growth and differentiation of hES cells. Clearly, this would be an enormous step forward towards clinical application of hES cells. In addition, some of the identified modified proteins can be used as markers for proteome-based screening of different hES cell types, which is critical when regenerative treatment is carried out. In summary, the proposed research will unravel the roles of the key cellular regulatory mechanism in hES cell biology. The outcome of the research can help to develop specific diagnostic tools and will also be important to the understanding and manipulation of hES cell differentiation.
Statement of Benefit to California:
This proposal will provide unique information of one of the key regulatory pathways controlling the fate of hES cells. The results will help to understand how hES cells is regulated regarding their growth, differentiation and survival. This is critical for generating specialized cell types for regenerative treatment for various human diseases such as diabetes, neurodegenerative disorders, heart diseases, etc. About half of California's families are estimated to have a member who could potentially benefit from stem-cell therapies. In addition, some of the identified modified proteins can be used as markers for proteome-based screening of different hES cell types, which is critical when regenerative treatment is carried out. Furthermore, the results will help us to determine conditions and design therapeutic agents to manipulate ubiquitination or sumoylation pathway to control the growth and differentiation of hES cells. We believe this would be an enormous step forward towards clinical application of hES cells. In summary, the scientific outcome of this proposal will provide a strong basis for inspiring biotech industry in California, providing job opportunities for Californian residents and stimulating economy growth. Exciting research in stem cells will also draw the best young scientists to the area to pursue career and advance science and medicine to keep California competitive in the field of regenerative medicine.