Deciphering intracellular signaling mechanisms in initial differentiation of hESC
It has been widely appreciated that human embryonic stem cells and somatic stem cells are expected to be sources of cells to regenerate or rejuvenate damaged tissues, yet the research work on human embryonic stem cells has been hindered by the difficulties in manipulating their self-renewal versus differentiation properties in vitro. This is largely due to lack of understanding of the molecular and cellular basis for maintenance of human embryonic stem cell pluripotency, the ability to duplicate itself and also give rise to other types of cells with specialized functions such as blood cells, neural cells in the brain and skeletal muscle cells.
Like many other cell types, the functions of human embryonic stem cells are regulated by extracellular signals. A unique intracellular signal transduction mechanism can interpret various extracellular signals, guiding the cell to adjust its activities for adaptation to the changes in the environment. One important biochemical mechanism for signal transduction is reversible phosphorylation on proteins, in which a phosphate can be added or removed from proteins. This reversible process is facilitated by two groups of enzymes, i.e. kinases that can add a phosphate on a protein and phosphatases that remove a phosphate from a protein. The applicant discovered a phosphatase that operates in the initial step of intracellular signal transduction more than a decade ago, published in Science, 1993. Notably, his group has found that removal of this phosphatase promotes mouse embryonic stem cell self-renewal. More recently, the applicant has also observed that this phosphatase has a similar function in human embryonic stem cells.
On this project, the applicant and his colleagues will use their expertise on stem cells to investigate and illuminate the biological properties of human embryonic stem cells. Based on the database accumulated from other research groups, this laboratory will do experiments and develop a better set of biological markers for identification of human embryonic stem cells.
Finally, the applicant and his colleagues will develop new reagents that can be used to amplify the human embryonic stem cells without changing its property in culture for basic research and clinical application.
This applicant must say at the outset that I am very proud of being an American, in particular a Californian. Californians have the tradition of stimulating an entrepreneurial spirit, thus making the state ahead of others to launch novel and risky ventures, particularly in the biotechnology field, and in the stem cell research. In the 21st century, there is no doubt that the research work on human embryonic stem cells will take the lead in the advancement of biomedicine and biotechnology. Progress in this type of research will benefit people suffering from many different types of diseases such as cancer, neurodegenerative diseases and cardiovascular disorders.
On the proposed project, the applicant and his colleagues will take advantage of decade-long research experience in molecular and cell biology, particularly on mouse and human embryonic stem cells. We will carefully investigate the human embryonic stem cell properties, to understand better how these cells can duplicate themselves and also produce other cell types with specialized functions, such as blood cells, neural cells and skeletal muscle cells. This information will be instrumental for future research and application of human embryonic stem cells in and outside of California.
Based on experimental results from this and other laboratories, we will be able to develop a better set of biological markers for identification of human embryonic stem cells. Finally and most importantly, we will design and produce new reagents that can be widely used in culturing and amplification of human embryonic stem cells for basic research and clinical application. All this will benefit tremendously Californians and people in this country, and in the world.