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

为了研究使用遗传修饰的iPS细胞是否可以绕过使用胎儿细胞移植所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ES和iPS细胞，这些细胞在移植到偏侧帕金森病小鼠的大脑中时，可以提高其治疗价值。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集落来产生遗传改变的小鼠ES和iPS细胞系。例如，在先前的研究中，我们已经显示了多巴胺神经元中基因PTEN（磷酸酶和张力蛋白同系物）的消融，导致多巴胺肥大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，该群体经遗传操作以消除多巴胺神经元中的PTEN活性。将缺乏PTEN活性的分化的多巴胺细胞移植到偏侧帕金森病小鼠的脑中，以研究这种策略对多巴胺富集和移植细胞的存活以及多巴胺能功能的替代的益处。

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.