Genetically mofidied stem cells: Can we improve stem cell replacement therapies?

为了研究使用转基因iPS细胞是否可以解决胎儿细胞移植带来的一些后勤问题，我们建议研究是否有可能操纵多巴胺-神经元分化和存活的机制，以产生转化的胚胎干细胞和iPS细胞，在移植到半帕金森小鼠大脑时提高其治疗价值。基因改变的小鼠ES和iPS细胞系将通过使用具有已知影响多巴胺细胞功能的特定突变的小鼠菌落来产生。例如，在之前的一项研究中，我们发现多巴胺神经元中PTEN基因（磷酸酶和紧张素同源物）的消融会导致多巴胺肥厚效应和神经元保护的显著增加。我们将从一个已建立的转基因小鼠群体中产生小鼠ES和iPS细胞，通过基因操纵来消除多巴胺神经元中的PTEN活性。将缺乏PTEN活性的分化多巴胺细胞移植到偏瘫小鼠的大脑中，研究这种策略对移植细胞多巴胺富集和存活以及多巴胺能功能替代的益处。

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.