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

转基因干细胞：我们可以改进干细胞替代疗法吗？

• 批准号: 8553293
• 负责人: Cristina Backman
• 金额: $ 42.84万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8553293
• 关键词: Ablation; Adult; Affect; Area; Biopsy; Brain; Bypass; Cell Line; Cell Therapy; Cell Transplants; Cells; Clinical Treatment; Clinical Trials; Corpus striatum structure; Development; Dopamine; Engineering; Gene Mutation; Genes; Genetic Engineering; Human; Immune system; Inflammatory Response; Laboratories; Methods; Motor; Mus; Mutation; Nerve Tissue; Neurodegenerative Disorders; Neuronal Differentiation; Neurons; PTEN gene; Parkinson Disease; Pathology; Patients; Phase; Pluripotent Stem Cells; Population; Proliferating; Regulator Genes; Replacement Therapy; Research; Research Personnel; Skin; Somatic Cell; Source; Stem cells; Substantia nigra structure; Symptoms; Technology; Therapeutic; Transgenic Mice; Transplantation; base; dopaminergic neuron; fetal; fetus cell; human disease; improved; induced pluripotent stem cell; interest; method development; neuronal survival; pars compacta; stem; treatment strategy

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.

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。

项目成果

Selective deletion of PTEN in dopamine neurons leads to trophic effects and adaptation of striatal medium spiny projecting neurons.

• DOI: 10.1371/journal.pone.0007027
• 发表时间: 2009-09-11
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Diaz-Ruiz O;Zapata A;Shan L;Zhang Y;Tomac AC;Malik N;de la Cruz F;Bäckman CM
• 通讯作者: Bäckman CM