Derivation of new induced pluripotent stem (iPS) cells to build neurological disease models

Funding Type: 
New Cell Lines
Grant Number: 
RL1-00677
Investigator: 
ICOC Funds Committed: 
$0
Public Abstract: 
Embryonic stem cells (ESCs) hold great potential for cell replacement therapies, in which the cells are lost due to disease or injury, since they are capable of proliferating perpetually and differentiating into multiple cell types depending on environmental and genetic factors. Despite the therapeutic potential of human embryonic stem cells (hESCs), clinical applications could be limited because of immune rejection. In addition, the use of hESCs has been the central focus of many ethical and political discussions. Therefore, many scientists, including us, have been searching for alternative sources for pluripotent stem cells. Recently, it has been shown that pluripotent stem cells (referred to as "iPS cells) can be obtained from somatic cells such as fibroblasts. The generation of iPS cells has created significant amount of excitement in the stem cell biology field, since it offers the possibility of creating stem cells from the somatic cells of the same individual. This approach not only circumvents the immune rejection problem but also the ethical concerns. However, it is not yet known whether iPS cells behave like hESCs functionally. Furthermore, differentiation of iPS cells into the cells of the central nervous system, such as neurons or glia, has not been demonstrated. In this application, we propose to derive patient-specific iPS cells from fibroblasts using alternative methods, to improve quality, safety, and test functionality while establishing in vitro models to study underlying molecular mechanisms of neurological diseases. Our laboratory has extensive expertise in handling hESCs. We created a highly efficient method to differentiate hESCs into neurons or glia. First, we will compare the functionality of iPS cells and hESCs. Using our established protocol, we will subsequently differentiate iPS cells into neurons. The characteristics of iPS cell-derived neurons will be documented using numerous techniques. Following the successful generation and characterization of iPS cell-derived neurons, we will begin to generate disease-specific iPS cells. We will collect dermal samples from Parkinson, Huntington and Rett Syndrome patients, since all three conditions have defined genetic alterations. The results of these experiments will allow us to use iPS cell-generated neurons as models to study underlying molecular mechanisms of neurological diseases. Ultimately, we will use these disease models to begin developing therapeutic approaches.
Statement of Benefit to California: 
Despite the therapeutic potential of human embryonic stem cells (hESCs), clinical applications could be limited because of immune rejection and ethical concerns. Recently, it has been shown that pluripotent stem cells (referred to as "iPS cells) can be obtained from somatic cells such as fibroblasts as an alternative source of pluripotent stem cells. This approach not only circumvents the immune rejection problem but also the ethical concerns. However, it is not yet known whether iPS cells behave like hESCs functionally. In this application, we propose to derive disease-specific iPS cells from fibroblasts taken from patients with Parkinson's disease, Huntington's disease or Rett Syndrome. The results of these experiments will allow us to use iPS cell-generated neurons as models to study underlying molecular mechanisms of neurological diseases. Ultimately, we will use these disease models to begin developing therapeutic approaches. Many Californians suffer from diseases that can possibly be cured by using stem cell technology. In this proposal, we designed experiments to create new stem cells using skin cells (i.e., fibroblasts). With this approach, we can study the underlying mechanism of many neurological disorders, such as Parkinson's disease (PD). PD is the second leading neurodegenerative disease, and there is no cure currently available. In comparison to other states in the U.S., California is among one of the states with the highest incidence of PD. The genetic component of the PD has been established. Using the proposed models of iPS cells of this application, we will begin to understand the etiology of PD. Better understanding of the genetics of PD will assist us to reveal how environmental factors participate in the development of PD. California growers use approximately 250 million pounds of pesticides annually, about a quarter of all pesticides used in the U.S. (Cal Pesticide use reporting system). A commonly used herbicide, paraquat, has been shown to induce parkinsonism in both animals and human. It has been shown that the incidence of PD-caused mortality was higher in counties where agricultural pesticide are used in comparison to the counties that do not use pesticides in California. Furthermore, California has the largest Hispanic population in the U.S. Studies suggest that incidence of PD is the highest among Hispanics (Van Den Eeden et al, American Journal of Epidemiology, Vol. 157, pages 1015-1022, 2003). Thus, finding effective treatments for neurodegenerative and genetic disorders, such as -but not limited to- PD, will significantly benefit the citizens of California.

© 2013 California Institute for Regenerative Medicine