Funding Type: 
SEED Grant
Grant Number: 
ICOC Funds Committed: 
Disease Focus: 
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
In diseases of the nervous system such as Parkinson’s disease (PD) and Lou Gehrig’s disease very specific groups of nerve cells die. At least in the case of PD, the surgical methods exist for the implantation of new cells into the area of the brain where the nerve cells are dying. However, since fetal brain cells are almost impossible to obtain, a viable and untested potential source of brain neurons are human embryonic stem (ES) cells. In order to get these cells to function in the brain, it is mandatory that the ES cells be converted to nerve cells before they can be surgically implanted. In our past work with rat and mouse stem cells we have been able to identify and purify factors that are made by nerve precursor cells that cause stem cells to become neurons. In addition, we have a very large potential source of these types of factors that is unique to our laboratory. Finally, we have identified a new family of drugs that may help keep the ES cell-derived neurons alive when they are transplanted into the brain, a situation in which most of them normally die. Therefore, the goal of this proposal is to identify new factors that convert human ES cells to specific types of neurons and to test the new family of compounds to determine if they promote the survival of ES cell-derived neurons in the brain.
Statement of Benefit to California: 
Our work will benefit the State in a number of ways. 1) There could be a tremendous health benefit for individuals with diseases of the brain such as Parkinson’s and Lou Gehrig’s diseases as well as damage due to stroke or trauma. 2) Support for this work will provide current employment within the State and help educate scientists in the stem cell field. 3) The advancement of work on novel growth factors and drugs will require the collaboration with commercial (for profit) companies. Most of early stage preclinical development is done in small biotech companies, many of which are within the State. Therefore, there is an economic benefit to the State as well as a health benefit to the State and the world if some of the most debilitating human diseases could be cured.
Progress Report: 
  • Human embryonic stem cells (hESCs) hold promise for treating a broad range of human diseases. However, at the time when we submitted this proposal, there was a striking paucity of published studies on how the fate of hESCs is controlled. For instance, we know that hESCs can form tumors upon transplantation, but the mechanisms governing cell division in these cells were still largely unknown. Given the central role of the retinoblastoma (RB) family of genes at the interface between proliferation and differentiation, our goal was to study the function of RB and its family members p107 and p130 in human embryonic stem cells (hESCs). In the last two years, we have examined the consequences of altering the function of RB, p107, and p130 for the proliferation, self-renewal, and differentiation potential of hESCs.
  • We have found that overexpression of RB results in cell cycle arrest in hESC populations, indicating that the RB pathway can be functionally activated in these cells. We have also found that loss of RB function does not result in significant changes in the biology of hESCs. In contrast, inactivation of several RB family members at the same time leads to self-renewal, proliferation, and differentiation defects.
  • Together, these studies indicate that the level of activity of the RB family is critical in hESCs: too much or too little RB family function results in loss of proliferative potential.
  • Our future goal is to precisely manipulate the levels of RB family genes to determine if we can identify conditions to manipulate the fate of hESCs, reducing their ability to proliferate (suppressing cancer) while allowing them to differentiate into specific lineages.

© 2013 California Institute for Regenerative Medicine