To investigate if the use of genetically modified iPS cells can get around some of the logistical problems imposed by the use of fetal cell transplants, we propose to study if it is possible to manipulate the mechanisms of dopamine-neuronal differentiation and survival in our favor, to generate transformed ES and iPS cells that enhance their therapeutic value when transplanted into the brain of hemiparkinsonian mice. Genetically altered mouse ES and iPS cell lines will be generated by using mouse colonies with specific mutations known to affect the function of dopamine cells. For example, in a previous study we have shown ablation of the gene PTEN (phosphatase and tensin homolog) in dopamine neurons, leads to dopamine hypertrophic effects and a significant increase in neuronal protection. We will generate mouse ES and iPS cells from an established transgenic mouse colony genetically manipulated to ablate PTEN activity in dopamine neurons. Differentiated dopamine cells lacking PTEN activity will be transplanted in the brain of hemiparkinsonian mice to study the benefits of such strategies for dopamine enrichment and survival from transplanted cells and replacement of dopaminergic function.
|Good, Cameron H; Hoffman, Alexander F; Hoffer, Barry J et al. (2011) Impaired nigrostriatal function precedes behavioral deficits in a genetic mitochondrial model of Parkinson's disease. FASEB J 25:1333-44|
|Diaz-Ruiz, Oscar; Zapata, Agustin; Shan, Lufei et al. (2009) Selective deletion of PTEN in dopamine neurons leads to trophic effects and adaptation of striatal medium spiny projecting neurons. PLoS One 4:e7027|