关于药物筛选

hygene

利用从罕见神经系统疾病患者身上产生的干细胞，科学家们正在解析该种疾病的发病原理，并以此来测试若干候选药物的疗效。发表在2009年8月20日《自然》杂志上的该项研究致力于实现干细胞研究的主要目标之一，即利用源于成体细胞重组的干细胞——诱导多能干细胞（iPS）来研究患者自体细胞疾病的影响，这种细胞是用其他方式所无法获得的。
6 M! @6 O) n* l( n. c/ ^细胞分析是药品研制过程中最关键也是最难解决的问题之一。细胞分析做得不好，就会增大研制成本，就会失去无数的机会。现已出现的微阵列法、荧光显微镜法、RNAi分析法、新一代流式血细胞计数法以及其他相关的细胞分析方法，为研究人员提供了一条更清晰地观察细胞活动从而更好地选择新药的途径。这些突破性进展使基于细胞分析的药物筛选方法变得更快捷、更简便、更有效。& v$ Z& }- @5 L; N1 N3 W
原文：Nature 461, 402-406 | doi:10.1038/nature08320: O& |7 G5 U) O  g5 L

- s& p' J+ D5 Q% ?# S' n/ Y7 U  }8 i. zModelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs
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  f& ~3 X# _3 F" {Gabsang Lee1, Eirini P. Papapetrou2, Hyesoo Kim1, Stuart M. Chambers1, Mark J. Tomishima1,2,3, Christopher A. Fasano1, Yosif M. Ganat1,6, Jayanthi Menon4, Fumiko Shimizu4, Agnes Viale5, Viviane Tabar2,4, Michel Sadelain2 & Lorenz Studer1,2,4- R" @5 U# |4 P9 U' r* C  V
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1 Developmental Biology Program,! x) H2 ^8 H5 g
2 Center for Cell Engineering,# k9 R* `& E; ?0 s
3 SKI Stem Cell Research Facility,& y" s1 ^, Z, c3 r8 L$ ^& v
4 Department of Neurosurgery,
& O( Q& `: H- v9 X3 }5 Genomics Core Facility, Sloan-Kettering Institute, 1275 York Ave,
5 |8 J- @8 S' m  ^" }+ L$ \6 Weill Cornell Graduate School, New York, New York 10065, USA
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3 K! I2 |7 W* S) l8 V6 i1 rThe isolation of human induced pluripotent stem cells (iPSCs)1, 2, 3 offers a new strategy for modelling human disease. Recent studies have reported the derivation and differentiation of disease-specific human iPSCs4, 5, 6, 7. However, a key challenge in the field is the demonstration of disease-related phenotypes and the ability to model pathogenesis and treatment of disease in iPSCs. Familial dysautonomia (FD) is a rare but fatal peripheral neuropathy, caused by a point mutation in the IKBKAP 8 gene involved in transcriptional elongation9. The disease is characterized by the depletion of autonomic and sensory neurons. The specificity to the peripheral nervous system and the mechanism of neuron loss in FD are poorly understood owing to the lack of an appropriate model system. Here we report the derivation of patient-specific FD-iPSCs and the directed differentiation into cells of all three germ layers including peripheral neurons. Gene expression analysis in purified FD-iPSC-derived lineages demonstrates tissue-specific mis-splicing of IKBKAP in vitro. Patient-specific neural crest precursors express particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis is further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behaviour. Furthermore, we use FD-iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Our study illustrates the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment.. k( N+ r+ f9 X5 g8 a. ?! d
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