Using induced pluripotent stem cells to identify cellular phenotypes of autism

精神疾病是毁灭性的，人们对此知之甚少。这个项目的目标是 确定自闭症和其他精神疾病的细胞生物学表型 疾病，利用人类干细胞技术的新发展。我 建议采集自闭症患者的皮肤成纤维细胞，将这些细胞重新编程为 诱导多能干细胞(IPS)，并将其分化为 神经元。然后，我将使用一套半自动的体外分析来开发一种表型 每个细胞系的指纹图谱侧重于发育和功能表型 很可能会导致自闭症。我们将使用自动显微镜、细胞分选器和 半自动膜片钳测量分化、迁移、存活、 患者来源的神经元的形态和兴奋性。最后，我们将带着 一些自闭症患者可获得的遗传信息的优势 是否特定基因的缺失、复制或突变导致了表型 在那个病人的神经元中观察到。这种方法有可能 使我们对自闭症和其他精神障碍的研究发生革命性变化。它将允许我们链接 引起细胞生物学缺陷的患者的表型和基因型 疾病。此外，它将使我们能够开发基于细胞的分析来研究 研究这种疾病的病因，并为这些无法治愈的疾病找到新的治疗方法。

Psychiatric diseases are devastating and poorly understood. The goal of this project is to identify the cell biological phenotypes that underlie autism and other psychiatric disorders, taking advantage of new developments in human stem cell technology. I propose to harvest skin fibroblasts from patients with autism, to reprogram these cells to generate induced pluripotent stem (iPS) cells, and to differentiate the iPS cells into neurons. I will then use a set of semi-automated in vitro assays to develop a phenotypic fingerprint for each cell line focusing on the developmental and functional phenotypes that are likely to lead to autism. We will use automated microscopes, cell sorters and semi-automated patch clamps to measure the differentiation, migration, survival, morphology, and excitability of neurons derived from patients. Finally, we will take advantage of the genetic information available for some autistic patients to determine whether deletion, duplication, or mutation of specific genes leads the phenotypes observed in the neurons from that patient. This approach has the potential to revolutionize our study of autism and other psychiatric disorders. It will allow us to link the phenotype and genotype of patients with the cell biological defects that give rise to disease. In addition, it will allow us to develop cell-based assays to both investigate the etiology of the disease and to find new treatments for these untreatable disorders.